mechanisms of distal axonal degeneration in peripheral ... · post-infectious neuropathy abstract...

Neuroscience Letters 596 (2015) 33–50

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Neuroscience Letters

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Review

Mechanisms of distal axonal degeneration in peripheral neuropathies

Christopher R. Cashmana,b, Ahmet Hökea,∗

a Departments of Neuroscience and Neurology, USAb MSTP- MD/PhD Program, Johns Hopkins University, Baltimore, MD 21205, USA

a r t i c l e i n f o

Article history:Received 27 October 2014Received in revised form 16 January 2015Accepted 19 January 2015Available online 21 January 2015

Keywords:Peripheral neuropathyGuillain–Barré syndromeDiabetesHIV neuropathyMitochondrial agingCampylobacter jejuniChemotherapy induced peripheralneuropathyWldS

Mechanisms of neuropathyPost-infectious neuropathy

a b s t r a c t

Peripheral neuropathy is a common complication of a variety of diseases and treatments, including dia-betes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). Despitethe fundamental difference between these insults, peripheral neuropathy develops as a combinationof just six primary mechanisms: altered metabolism, covalent modification, altered organelle functionand reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonaltransport, and altered ion channel dynamics and expression. All of these pathways converge to lead toaxon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itselfhave begun to be elucidated with studies of animal models with altered degeneration kinetics, includ-ing the slowed Wallerian degeneration (WldS) and Sarm knockout animal models. These studies haveshown axonal degeneration to occur through a programmed pathway of injury signaling and cytoskeletaldegradation. Insights into the common disease insults that converge on the axonal degeneration pathwaypromise to facilitate the development of therapeutics that may be effective against other mechanisms ofneurodegeneration.

© 2015 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341.1. Clinical overview of selected diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

1.1.1. Diabetic neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341.1.2. Chemotherapy induced peripheral neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341.1.3. Human immunodeficiency virus neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341.1.4. Non-HIV infectious causes: hepatitis C and Campylobacter jejuni . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2. Mechanisms of peripheral neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352.1. Metabolic dysregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2.2. Covalent modification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352.3. Organelle damage and reactive oxygen species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

2.3.1. Impaired mitochondria function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372.3.2. Endoplasmic reticulum dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382.3.3. Reactive oxygen and nitrogen species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

2.4. Intracellular and inflammatory signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392.5. Axonal transport defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412.6. Channelopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Abbreviations: AGE, advanced glycation end products; AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AMAN, acute motor axonal neuropathy; CIDP,chemotherapy induced peripheral neurotoxicity; ddC, 2′ ,3′-dideoxycytidine; ETC, electron transport chain; G6P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydro-genase; GBS, Guillain–Barré syndrome; HCV, hepatitis C virus; IGF-1, insulin-like growth factor-1; IFN-�/�, interferon � or �; MPTP, mitochondrial permeability transitionpore; Nmnat, nicotinamide mononucleotide adenylyltransferase; PARP, poly(ADP-ribose) polymerase; RAGE, receptor of advanced glycation end products; RNS, reactivenitrogen species; ROS, reactive oxygen species; TLR, toll-like receptor; Ube4b, ubiquitination factor E4B; WldS, slowed Wallerian degeneration gene.

∗ Corresponding author at: Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe St., Rangos 248, Baltimore, MD 21205, USA.Tel.: +1 410 955 2227.

E-mail address: [email protected] (A. Höke).

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34 C.R. Cashman, A. Höke / Neuroscience Letters 596 (2015) 33–50

3. New insights into mechanisms of degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

1. Introduction

Peripheral nerve degeneration is a common disorder of thenervous system whereby sensory and/or motor axons no longereffectively communicate between the periphery and central ner-vous system. The prevalence of peripheral neuropathy in the UnitedStates has been reported to be nearly 15% in adults over the age forty[108].

Peripheral neuropathy is not a single, homogenous disease,but is instead a mix of different clinical presentations, naturalhistories, and pathologies. Patients may present with motor insuffi-ciency (weakness), sensory abnormalities (numbness, paresthesias,hyperalgesia/allodynia, pain), autonomic symptoms, or a combi-nation of all, often depending on the particular disease. Thesevarious constellations of neurological symptoms suggest motor,sensory, and autonomic axons have differing susceptibilities tovarious disease processes. Additionally, while most neuropathiesare chronic, slowly progressive conditions, some neuropathieshave a more acute onset and gradual recovery [111] (reviewedin [140,275,293]). The heterogeneity of peripheral neuropathiesis likely secondary to the initiating event. Few neuropathies arepresent in isolation, but, rather, are often secondary to other sys-temic illnesses, including diabetes and infectious causes such ashuman immunodeficiency virus and hepatitis C virus. Additionally,peripheral neuropathies may be iatrogenic, arising from the toxicityof drugs given as part of antiretroviral or chemotherapy regiments.

Despite the great variety of cause and symptoms, the patho-physiology of peripheral neuropathies is limited to only a handfulof mechanisms. In this article, the pathophysiological mechanismsof various types of peripheral neuropathy – diabetic neuropathy,chemotherapy induced peripheral neurotoxicity (CIPN), HIV- andnon-HIV infectious neuropathies – will briefly be reviewed in aneffort to examine how many different disease process convergeonto a handful of cellular targets involved in the axonal degradationpathway to produce peripheral nerve dysfunction. As it is amongthe most heavily studied, diabetic neuropathy will serve as the pro-totypical example for many of the mechanisms, then additionaldetail added for particular diseases.

1.1. Clinical overview of selected diseases

1.1.1. Diabetic neuropathyDiabetes mellitus is a very common chronic disease. In 2014,

over 9% of the United States population (21 million people) hasbeen diagnosed with diabetes [47], and the prevalence is expectedto increase [220]. Diabetes is the most common cause of peripheralneuropathy, accounting for over half of the cases in a recent Dutchstudy [207].

Diabetic peripheral neuropathy is classically a sensory neuropa-thy presenting as numbness and paresthesias in a length dependent“stocking glove” distribution, whereby the feet are affected earlierand more severely than the hands (as reviewed in [51]), but painful,autonomic, or motor neuropathies may also occur (reviewed in[249]). In two studies of patients with type-I diabetes, intense glu-cose control reduced the risk of peripheral neuropathy by 60%[102,110]. This finding suggests that the elevated glucose levelsin the body may be pathogenic. While hyperglycemia may bea large component of the pathogenesis of diabetic neuropathy,non- hyperglycemic effects of diabetes, including reduced trophic

support (hypoinsulinemia in type I and advanced type II diabetes)and mitochondrial health and function, may also be important.

1.1.2. Chemotherapy induced peripheral neurotoxicityWhile improved cancer treatment regimes and higher rates of

remission are a boon to modern medicine and cancer biologists,many of the commonly used anti-neoplastics have long term toxiceffects that currently are not well mitigated during treatment [45].Indeed, chemotherapy induced peripheral neurotoxicity (CIPN) hasincreased in incidence as cancer remission rates continue to climbdue to improved cancer therapies (as reviewed in [12,45]). Whilethe incidence and prevalence of CIPN varies by agent, in general,30–80% of treated patients develop a peripheral neuropathy (asreviewed in [96]). Patients experience motor and sensory symp-toms, including numbness, pain, and weakness [248], so severelythat they may be dose-limiting. The wide variety of symptomssuggests chemotherapeutic agents may harm multiple types ofneurons, as well as different parts of neurons, including the axon(axonopathy) or the soma/ganglion (ganglionopathy) (as reviewedin [118]). The most common causes of CIPN include taxanes, suchas paclitaxel, platinum agents including cisplatin and oxaloplatin,and proteasome inhibitors such as bortezomib and will, thus, bethe focus of discussion. For other compounds, readers are referredto Argyriou et al’s excellent, recent review [12]. Within a pharma-cological class, there is also heterogeneity. For example, cisplatinhas chiefly chronic affects, but oxaliplatin has toxic neurologicaleffects in both the acute and chronic setting, suggesting differentprocesses may underlie early and late pathology. Thus, the partic-ular pathophysiology of CIPN depends not only on the family ofchemotherapeutic but also on the specific member of the family.

1.1.3. Human immunodeficiency virus neuropathyThe global prevalence of the human immunodeficiency virus

(HIV) in 2009 was found to be 33.3 million [1], and nervous sys-tem defects, including a peripheral neuropathy, is common inthe disease [159,229]. Interestingly, while control of the virus hasimproved over the past few decades, the incidence of neuropathyhas increased from 13% in 1993 to 42% in 2006 [229]. This increasein prevalence during the era of effective treatments suggests thatthe neuropathy is not caused by the virus alone, but also by thedrugs used to treat it [87]. HIV neuropathy is chiefly a sensoryneuropathy of pain, paresthesias, and absent ankle reflexes [67].Direct viral infection of neurons or Schwann cells has not been welldemonstrated, but the virus has been recovered from some nervesamples [52,74]. Viral concentration in these samples is remarkablylow, suggesting viral particles and proteins must enter the nervethrough other cells, such as macrophages or T-cells. Indeed, carefulstudies of viral tropism have shown that particles recovered fromnerve are consistent with macrophage and T-cell infectious par-ticles, [127] and that viral proteins colocalize with macrophagesin vivo [115]. These findings suggest the virus is brought to thenerve by immune cells, but does not directly infect neuronal cells[66,115]. The viral proteins gp120 and protein R (VPR) are espe-cially important toward the observed neurotoxicity. The primarymechanisms of the neuropathy appear to be immune damage fromviral proteins and mitochondrial toxicity from the antiretrovirals(as reviewed in [131,133]).

C.R. Cashman, A. Höke / Neuroscience Letters 596 (2015) 33–50 35

1.1.4. Non-HIV infectious causes: hepatitis C and Campylobacterjejuni

In addition to HIV, hepatitis C virus (HCV) and C. jejuni infectionare also associated with peripheral neuropathy. Hepatitis C is a viralinfection that may become an intractable, chronic infection, bestknown for causing liver cirrhosis and hepatocellular carcinoma.In 2011, the best estimate of prevalence was 2.35% of the worldpopulation (160 million people), making it five times more com-mon than HIV [143]. HCV has long been known to be associatedwith neurological complications including peripheral neuropa-thy and encephalopathy [241]. A study in France of 321 patientswith hepatitis C infection found 9% and 10% develop a sensoryor motor neuropathy, respectively [40]. HCV-associated periph-eral neuropathy has been further divided into four subtypes basedon distribution: polyneuropathy, mononeuritis multiplex, cranialneuropathy, and a combination of polyneuropathy/cranial neu-ropathy, with axonal degeneration and demyelination on biopsy[180]. Importantly, the hepatitis C virus has not been shown toreplicate or infect muscle or nerves directly [14], so, as was the casewith HIV, neuropathy must develop through indirect, inflammatorymechanisms instead of direct viral infection.

In these studies of HCV and peripheral neuropathy, cryoglobu-linemia was found to alter the complication profile associated withHCV infection [40] and be associated with more widespread neu-ropathy [180]. Cryoglobulins are immunoglobulins that reversiblyaggregate at cooler (less than 37 ◦C) temperatures and are associ-ated with a variety of chronic and autoimmune diseases, with HCVinfection being one of the best characterized (as reviewed in [95]).Between 30 [213] and 78% [180] of patients with HCV have beenreported to have cryoglobulinemia. Although the presence of cryo-globulinemia as a risk factor for neuropathy has been debated, it isinteresting to consider Nemni, et al’s findings that, while cryoglob-ulinemia may not increase the severity of neuropathy, it changesthe profile to one of a more generalized syndrome [180]. This obser-vation is pertinent since cryoglobulinemia is known to lead tosystemic vasculitis, suggesting ischemic injury and inflammationmay be important for the development and/or advancement of HCVinduced peripheral neuropathy [14] .

The bacteria C. jejuni is a common cause of gastroenteritis andis associated [100] with a post-infectious neuropathy in 1 of 1000infections [5]. First described by Guillian, Barré, and Strohl [111],the neuropathy often occurs a week after infection and is classi-cally an acute, ascending, motor neuropathy (as reviewed in [275]).With an estimated incidence of 1/100,000 [5], Guillian–Barré syn-drome (GBS) is somewhat rare but may cause permanent disabilityor be fatal secondary to diaphragmatic paralysis and respiratoryfailure [275]. While some viruses may also cause GBS, C. jejuni isbelieved to cause 30% of all cases [5]. GBS has recently been appreci-ated to have multiple subtypes [275], including acute inflammatorydemyelinating polyradiculoneuropathy (AIDP) and acute motoraxonal neuropathy (AMAN) [109,119,162]. The pathophysiology ofAMAN is more thoroughly understood than AIDP, and, thus will beused to discuss principles that may be generalized to other sub-types.

2. Mechanisms of peripheral neuropathy

2.1. Metabolic dysregulationIn diabetes, hyperglycemia leads to dysregulation of the

polyol, hexosamine, and pentose phosphate pathways that ulti-mately leads to reactive intermediates that damage the axon andSchwann cells. Glucose-6-phosphate (G6P) can be diverted by theenzyme glucose-6-phosphate dehydrogenase (G6PD) from glycol-ysis into the anaerobic pentose phosphate pathway to producemore NADPH. When intracellular glucose (and, thus, glucose- 6-phosphate) levels are very high, G6PD is inhibited [300], and

glucose is instead diverted into the polyol pathway by the enzymealdose reductase to produce the alcohol sorbitol (see Fig. 1). Sorbitoland other polyols accumulate in various tissues throughout thebody, including the sciatic nerve of experimental rat models [101].Sorbitol reduces the level of membrane component myo-inositolin cultured neuroblastoma cells exposed to high levels of glucoseby inhibiting its cellular import [290]. This disruption of the axonalmembrane could reduce the ability of the axon to propagate anaction potential [290] or impair the ability to regenerate followinginjury since a “wave” of lipogenesis is necessary for regeneration[156], and nerves from patients with diabetes demonstrate areasof focal demyelination and remyelination, a lipid intensive process[245]. Additionally, myo-inositol depletion in a rat model of type IIdiabetes is associated with reduced Na+-K+-ATPase activity, leadingto a nerve conduction deficits [107].

NADPH is one of the primary intracellular antioxidants, so itsdepletion reduces the ability of a cell to protect against oxidantdamage, ultimately leading to apoptosis. The polyol pathway alsodepletes NADPH, since it is used in the conversion of glucose intosorbitol (see Fig. 1). The pentose phosphate pathway is an anaero-bic metabolic pathway used to create NADPH reducing equivalentsand other biomolecules. G6PD is the gateway to this pathway, soits inhibition by high glucose levels is a second hit against theproduction of antioxidants, ultimately leading to increased ratesof apoptosis [247,300]. Thus, dysregulation of the polyol path-way by hyperglycemia may cause nerve damage through multiplemechanisms: membrane damage by reduced levels of myoinos-itol, and increased radical damage from a reduced antioxidantcapacity.

2.2. Covalent modification

In addition to the potential toxicity from alternative metabolicpathways in diabetes, glucose itself can be toxic as a result ofnon-enzymatic addition of glucose to proteins via the Amadoriproduct [6] of the Maillard reaction [155] whereby glucose con-denses with the amine group of amino acids to form modifiedproteins, “advanced glycation end products” (AGEs), as reviewedin [35]. AGEs have been observed in both the axons and Schwanncells of peripheral nerves, with enrichment of AGEs in samplesfrom patients and animal models of diabetes [261,234,84]. Thesemolecules work through direct modification of biomolecules.

Among the modified proteins is collagen, which leads toincreased thickness [240], immune complex deposition [36], andLDL trapping in vitro [37] in comparison to non-modified colla-gen. All of these are characteristics of an atherosclerotic plaque,which can lead to luminal narrowing of a vessel and greater riskof occlusion, thereby reducing blood flow and exposing the nerveto hypoxic conditions. This hypoxic risk is increased by AGEs thatquench the vasodilator nitric oxide released from endothelial cells[38], demonstrating how multiple aspects of the response to hyper-glycemic synergize to damage tissue.

One of the principal components of the basement membrane,laminin is critical for the health and development of neuronsand Schwann cells (as reviewed in [62]) and is directly modi-fied by AGEs. Modified laminin inhibits neurite outgrowth in vitrowhen compared to nonmodified laminin [90], and this reductionin outgrowth persists despite neurotrophin stimulation or precon-ditioning [84]. One can imagine the AGE modifications of collagenand laminin combining to produce recurrent injury to axons: themodified collagen facilitates hypoxic conditions which damagesthe axon, but the modified laminin is not permissive to axonregrowth, thereby limiting peripheral nerve recovery and produc-ing an axonopathy.

Glyceraldehyde-3- phosphate, a metabolic intermediate of thepolyol and glycolytic pathway, can nonenzymatically bind to, and,


Fig. 1. Summary of metabolic pathways. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)A variety of metabolic processes that branch off of glycolysis are dysregulated in diabetes, including the polyol, pentose phosphate, and hexosamine pathways. This dysreg-ulation leads to protein modification, changes in extra- and intra-cellular signaling (effectors in blue text), and decreased antioxidant capacity secondary to reduced NADPHlevels (shown in green). Red arrow indicates inhibition of the pentose phosphate pathway by elevated glucose levels.

thus interfere with, other proteins [42] (as reviewed in [246]).Glyceraldehyde-3-phosphate may also activate the protein kinaseC (PKC) pathway, since it can be degraded into diacylglycerol, oneof the secondary messenger of the canonical PKC signaling cascade[203]. This pathway has been shown to be particularly relevant forvascular complications associated with diabetes (as reviewed in[73]).

The hexosamine pathway produces glucosamine-6-phosphateand glutamate from fructose-6-phosphate and glutamine (seeFig. 1). Glucosamine-6- phosphate is ultimately converted intoUDP-N- acetylglucosamine (UDP-GlcNAc) and other hexosaminesto serve as substrates for glycoprotein sugar moieties (reviewed in[39]). UDP-GlcNAc can be covalently bound to proteins by O-GlcNActransferase. These modifications are believed to regulate proteinfunction by competing with kinase phosphorylation [63]. Indeed,O-GlcNAcylation has been observed on numerous proteins regulat-ing transcription, including RNA polymerase II [63], Sp-1 [287], andinsulin receptor substrates 1 and 2 (IRS1/2) [89]. In the case of Sp-1,O-GlcNAcylation leads to increased expression of more pathogenicproteins such as TGFß [81]. Thus, over activity of the hexosaminebiosynthetic pathway modifies the activity of numerous transcrip-tion factors, ultimately leading to gross changes in cell state andsignaling.

In addition to proteins, other biomolecules, such as DNA, canalso be modified by AGE products. Plasmid DNA incubated withreactive AGE products produced double strand DNA breaks andbase modifications [174]. A small study of 31 type II diabeticpatients in Turkey found higher AGE DNA adduct concentrationin patients with diabetes compared to controls, despite the use of

oral hypoglycemic drugs [198]. This study confirms the ability ofAGE compounds to react with other biomolecules in vivo as well asillustrates how modified molecules remain in the tissue despite ini-tiation of hypoglycemic therapy, although it remains unclear whateffect the modified DNA has in these tissues.

DNA modification is also believed to be one of the mecha-nisms responsible for the chronic symptoms of CIPN, particularlyfollowing treatment with platinum containing compounds like cis-platin and oxaliplatin. Incubation of DRG neurons in vitro withoxaliplatin and cisplatin decreases neurite outgrowth, increasesplatinum/DNA adducts [160,238], and apoptosis–mediated celldeath [238]. The exact mechanisms of toxicity is platinum adductformation with nuclear and mitochondrial DNA [160,197] whichinitiates apoptosis [161]. Interestingly, the increased accumulationof platinum/DNA adducts is selective for DRG neurons, over cancercells, in vitro [160], likely due to expression of a selective organiccation transporter [231]. This pattern may explain the particularvulnerability of sensory neurons to platinum compounds like cis-platin and oxaliplatin.

2.3. Organelle damage and reactive oxygen species

Mitochondria, the site of oxidative phosphorylation, are intrin-sically linked to the development of reactive oxygen species (asreviewed in [175]). Damage or pathology associated with theseorganelles may lead to cell death through apoptosis or ener-getic failure, thereby increasing sensitivity to ischemia. Given theconstant flux of electrons and oxygen in mitochondria, it is notsurprising that they are likely the primary site (more than 90%)


of reactive oxygen species production (as reviewed in [19]). Mito-chondrial dysfunction, both in its normal function and increasedROS production, has been implicated in the pathogenesis of manydifferent neuropathies.

In addition to mitochondria, (dys) function of the endoplas-mic reticulum also facilitates development of neuropathy. As afundamental component of the protein synthesis and modifica-tion pathway, insults that may inhibit the proteasome or increasethe concentration of unfolded proteins may trigger stress, therebyreleasing calcium and initiating the unfolded protein response,leading to cell death through multiple pathways (as reviewedin [282]). Impairment in both the endoplasmic reticulum andmitochondria are a common mechanism to all of the pathologiesdiscussed.

2.3.1. Impaired mitochondria functionWhile it is perhaps expected that mitochondria, as the pri-

mary energy production site for the mammalian cell, would displaycertain pathology in the setting of a hyperglycemia and aberrantmetabolism, recent work has suggested that the mitochondria playa much more active role in the development of neuropathy throughcell death and injury.

In a murine model of type II diabetes, Vincent et al., foundabnormal mitochondrial morphology in sensory neurons despitean increased mitochondrial density in their axons, neurites, and cellbodies compared to healthy control mice [86,255]. Vincent et al.,suggest increased mitochondrial fission is necessary to meet thegreater energetic requirements of a hyperglycemic state, but toorapid mitogenesis leads to unhealthy mitochondria [255]. Alterna-tively, mitochondria fission may represent a response to toxicity. Ina 2005 review, Youle and Karbowski proposed a model of the induc-tion of apoptosis whereby the machinery necessary for fission alsomediates apoptosis [145,291].

Mitochondrial dysfunction is also evident with an impaired res-piratory capacity. Indeed, in an animal model of type I diabetes,mitochondria in sensory neurons displayed depressed respiratoryfunction compared to control animals due to lower activity of com-plex I and IV secondary to reduced protein expression of certaincomplex components [56]. The reduced protein levels, in turn,are likely due to reduced PGC-1�/AMPK axis signaling that occursin the setting of hyperglycemia and metabolic derangement [55].Impaired electron transport chain function also causes an increasein ROS generation (as reviewed in [177]), which will be discussedin more detail later.

Mitochondrial dysfunction is a major mechanism of CIPN acrossall of the various chemotherapeutic agents. The taxane familyof chemotherapeutics, including paclitaxel, exercises its antineo-plastic effects through inhibition of tubulin depolymerization (asreviewed in [128]), thereby interfering with the stabile/labile bal-ance of microtubules [128], including the axons of neurons [17].Swollen and vacuolated mitochondria are commonly observed inthe axons of sensory nerves of animal models CIPN caused bypaclitaxel [98,279,280]. By interfering with microtubule dynam-ics, paclitaxel has been shown to interfere with calcium signalingin mitochondria and the endoplasmic reticulum by the opening ofthe mitochondrial membrane permeability pore, leading to calciumtriggered calcium release from the ER [135,171]. The opening ofthe mitochondrial permeability transition pore (MPTP) also leadsto release of ROS and cytochrome C [252]. For these reasons, theMPTP has been hypothesized to be a major, convergent effectorof axonal degeneration [21] via induction of apoptosis [205] anddownstream calcium activated effectors. The increase in calciummay also facilitate cellular injury by activating the calcium depen-dent protease calpain. Indeed, paclitaxel treated animals that werealso administered a calpain inhibitor displayed improved neuro-logical scores and fewer signs of sensory axon degeneration, even

though apoptotic rates were unaffected [270]. Furthermore, calpainalso degrades the neuronal calcium sensor-1 protein, leading toreduced IP3 signaling [27,28]. In addition to direct toxic and apop-totic effects, the abnormal mitochondria may also be pathogenicbecause of reduced respiratory ability, thereby contributing toenergetic failure [280,301].

Mitochondrial dysfunction has also been observed in axonsfollowing CIPN caused by oxaliplatin and bortezomib [279,301].Commonly used for multiple myeloma, bortezomib is a chemother-apeutic that inhibits the proteasome. Like platinum agents andtaxanes, it is well known to cause painful sensory neuropathy inhumans and animals [166]. Bortezomib, like paclitaxel, has beenshown to lead to mitochondrial calcium release leading to activa-tion of the apoptotic cascade [142] and energetic collapse [302].

In HIV neuropathy, both the virus and the drugs used to treatthe infection lead to mitochondrial dysfunction. When culturedDRG neurons were exposed to HIV infected macrophages, mito-chondrial membrane potential in the soma decreased as reactiveoxygen species formation increased, but there was no effect onneurite mitochondria, suggesting there are distinct mechanismsof injury between the soma and axon [115]. This separation hasbeen well characterized in studies on inflammatory and apoptoticsignaling (discussed below).

In addition to induction of apoptosis and increased calciumfrom the MPTP (as reviewed in [206]), mitochondria are func-tionally impaired because of damaged DNA. In a recent study ofsural nerve mitochondria in HIV patients with and without sen-sory neuropathy, mitochondrial deletions were more common inthose with neuropathy [144], with more mutations observed indistal mitochondria versus those in more proximal aspects [144].These mutations were correlated with reduced mitochondrial res-piratory function [144]. Interestingly, mitochondrial defects werenot observed in the proximal sciatic nerve, only the sural nerve,which suggests the distal aspect of specific types of axons are moresensitive to toxicity [144]. Lehman et al’s study of mitochondrialmutations and dysfunction lead to the development of a novel,unifying theory of neuropathy based on mitochondrial aging and,thus, distal axon susceptibility. Mitochondria must travel from thesoma to the periphery, which may take months to years. During thisprocess, mitogenesis takes place, but in an imperfect manner, lead-ing to an accumulation of mitochondrial DNA (mtDNA) mutations,and, thus deficits. This process would make the distal most aspectof an axon more susceptible to further injury than the proximalaspect, mirroring the length dependency of many neuropathies.Additionally, Lehman et al., also suggested that the higher density ofmitochondria in small, lightly or non-myelinated fibers [144] willmake these fibers especially sensitive to mitochondrial dysfunc-tion, as is observed with the primarily sensory component of manyneuropathies. Lastly, one can imagine that processes that affectaxonal transport will only exacerbate mitochondrial dysfunctiondistally since it takes longer to reach distal points. This hypothesisof mitochondrial aging is an exciting development toward a uni-fying explanation of many different peripheral neuropathies, butmore testing is needed, especially toward the development of ther-apeutics that protect mitochondria from chronic damage and aging.This hypothesis suggests that agents that directly damage mito-chondrial DNA may exacerbate neuropathic symptoms, and this isindeed what is observed in the treatment of HIV infection.

Mitochondrial dysfunction in HIV neuropathy occurs through avariety of antiretroviral treatments (as reviewed in [71]). Treatmentof rabbits with a nucleoside analog (2′,3′-dideoxycytidine;ddC)show robust dysmyelination, abnormal Schwann cell morphology,and slowing of nerve conduction velocity [9,91]. Treated patientsdisplay an increased density of swollen, vacuolated mitochon-dria with inclusions in the axons and Schwann cells of the suralnerves in those treated with ddC [72]. These abnormal mitochon-


dria correlate with a reduced level of mtDNA [72], likely as aresult of inhibition of mtDNA polymerase [158] (as reviewed in[130,131]) and subsequently reduced protein levels [144]. Thisreduced amount of mtDNA may exacerbate the mtDNA damagefrom aging as described in the hypothesis above. Indeed, the ratio ofmtDNA to nuclear DNA in nerve samples is reduced with infectionand drug over infection only, and marginally recovers upon drugcessation [68]. Like HIV itself, the antiretroviral-induced damageto mtDNA also leads to impaired mitochondria function.

Antiretrovirals are sufficient to interfere with mitochondrialfunction. By inhibiting replication of the mitochondrial genome,a number of the necessary components of the electron transportchain may not be produced, thereby leading to uncoupled trans-port and decreased oxidative phosphorylation, as is observed inneuronal mitochondria treated with ddC in vitro [132]. Interest-ingly, patients on nucleoside analogs often display hyperlactemia,which resolves upon drug cessation. One could imagine sys-temic mitochondrial inhibition would lead to decreased oxidativephosphorylation, and, thus a concomitant increase in glycolysisand lactic acid fermentation. Thus, antiretroviral drugs and HIVinfection synergize to cause greater injury [305]. As with otherneuropathies, mitochondrial dysfunction may cause additional cel-lular injury through the production of reactive radical species, asoutlined below.

2.3.2. Endoplasmic reticulum dysfunctionThe endoplasmic reticulum (ER) is also vulnerable to various

toxicities, as evidenced by the induction of the unfolded proteinresponse. While ER inhibition in diabetes is not well characterized,bortezomib has been shown to induce a transient stress responsein the Schwann cell ER, leading to myelination deficiency and anincreased cytokine expression [224]. This off target effect is perhapsunsurprising, given bortezomib’s mechanism of action as a protea-some inhibitor one would expect the unfolded protein response toincrease, as well.

While most of the work has examined mitochondrial dysfunc-tion in the setting of HIV neuropathy and anti-retroviral therapy,the ER may also be adversely affected by viral proteins. Indeed, ina study by Höke, et al., the HIV envelope protein gp120 inducedER calcium release by binding to the chemokine receptor to acti-vate the canonical IP3 signaling cascade leading to rapid increaseof intracellular calcium [123]. When calcium storage in the ER wasexperimentally reduced, the neurons were more resistant to gp120triggered cell death, reinforcing the important role of the ER inmediating degeneration [123]. A similar calcium response has beendescribed upon DRG neuron exposure in vitro to Vpr [2]. While thedownstream effect of the increased calcium has not been well stud-ied, one could imagine a similar mechanism to what is observed inCIPN with calpain protease activation and the induction of apopto-sis (as reviewed in [116]).

2.3.3. Reactive oxygen and nitrogen speciesThe electron transport chain (ETC) produces superoxide as a

byproduct of electron uncoupling followed by reduction of oxygento form the free radical [20], but mitochondria also produce hydro-gen peroxide, hydroxide radicals, and nitric oxide, all of which arereactive species that can directly damage other proteins or DNAthrough covalent modification (as reviewed in [177,227]). Whilesuperoxide production is a common feature of all eukaryotic cells,the nervous system may be particularly vulnerable to free radicaldamage because of large energetic demands and high lipid content(as reviewed in [168]).

Natural antioxidants help mitigate this damage, such that thedepletion of these molecules increases the susceptibility of thecell the oxidative damage. Uncoupling proteins serve to reducethe electrochemical potential across the mitochondrial inner mem-

brane by bypassing ATP synthase, thereby uncoupling the hydrogenion gradient from the generation of ATP (as reviewed in [208,228]).ROS generation may be reduced by uncoupling since the electrontransport chain (ETC) complexes that may generate superoxideradical are bypassed (as reviewed in [173,228]). The uncouplingprotein (UCP) family includes three proteins, UCP-1, UCP-2, andUCP-3, which are all hydrogen ion channels or transporters. UCP-1 was identified to be involved in thermogenesis from brown fat[181], while UCP-2 and UCP-3 were found [85] to be importantfor homeostasis [99] and thermogenesis [31] in a variety of tissuesincluding white adipose tissue and brain for UCP-2 [99] and DRG,brown adipose tissue, and skeletal muscle for UCP-3 [257,284].UCP-2 and UCP-3 were also quickly identified as inhibitors of ROSgeneration in the mitochondria [179,253], since null mice displayedevidence of increased ROS production and damage (as reviewed in[30]). UCPs are also critical for the attenuation of damage from ROSsecondary to hyperglycemia. A variety of studies have shown allthree UCP family members to protect cells from hyperglycemiainduced ROS generation when the proteins are overexpressed[209,257]. Interestingly, in the setting of hyperglycemia, UCP-3expression is actually reduced [257]. These data suggest develop-ment of damage secondary to hyperglycemia may be facilitated by areduction of UCPs in vivo, or, alternatively, loss of UCPs in vivo mayfacilitate the development of diabetic complications. This relation-ship makes UCP expression an enticing therapeutic target, but thedevelopment of drugs to alter expression must move forward withgreat caution since overexpression of UCP-2, for example, reducesinsulin secretion, thereby potentially worsening the hyperglycemiacharacteristic of diabetes [49,50]. Thus, while there is some conflict-ing evidence on the utility of increased UCP expression toward theprotection from, or development of, the complications of diabetes,there is clear evidence that the coupling of the ETC to ATP produc-tion becomes dysregulated in diabetes which may lead to increasedROS and altered energetics (as reviewed in [173]).

Superoxide production may be a unifying mechanism that initi-ates, or least propagates, many of the mechanisms of neuropathy indiabetes. The aforementioned pathogenic elements from metabolicderangements (sorbitol, AGEs, PKC signaling) decreased upon inhi-bition of superoxide [183]. Mitochondrial function and DNA healthwas also improved upon inhibition of superoxide production inthe retina in a model of diabetes [242] . The ROS control of thesemechanisms is effected by DNA damage activated poly(ADP-ribose)polymerase (PARP). PARP catalyzes the inhibitory ADP-ribosylationof proteins, including GAPDH [80] (as reviewed in [177]), inhibitionof which increases activity of the hexosamine pathway, PKC sig-naling activation, and AGE concentration [80]. Additionally, recentevidence has implicated PARP as not just a downstream signal ofoxidative damage, but, instead, as a promulgator of ROS damagein a variety of tissues, including Schwann cells and the peripheralnerve [185]. PARP is directly neurotoxic due to the depletion of itscofactor, NAD+, when it is catalytically active [113]. Severe reduc-tion of NAD+ results in energetic collapse of the cell and necroticdeath [113].

In addition to ADP- ribosylation, superoxide may directly oxi-dize proteins to form carbonyl adducts that may modify proteinfunction (as reviewed in [177]). Indeed, these modified proteinshave been identified in the brain [70,202], although their functionis not well studied. In addition to oxygen modification, ROS maylead to PARP mediated up regulation of iNOS followed by reactionof nitric oxide with superoxide to produce the reactive nitrogenradical [185]. Regardless of its source, nitric oxide may also modifyproteins [185] to act in both damaging and protective capacities[168]. Nitric oxide and its radical may be a particularly importantpathogenic mechanisms in the nervous system due to its use asboth a neurotransmitter by neurons and regulator of blood flowsecondary to nitric oxide mediated vasodilation [168]. The balance


between nitric oxide and its radical likely explains the observedprotective and damaging effects of nitric oxide, since nitric oxidewith its vasodilatory activity is likely protective, but its radical,that accumulates with increased ROS, likely mediates protein, and,thus, cellular, injury (as reviewed in [258]). Thus, the develop-ment of ROS and reactive nitrogen species (RNS) are a criticalcomponent of diabetes-induced damage that extends beyond sim-ple radical chemistry to prolonged alterations of cellular signalingpathways.

CIPN, like diabetes, is also mediated by ROS (as reviewed in [65]).Both oxaliplatin and cisplatin have been shown to generate ROS[126], and mitochondria are damaged by ROS/RNS secondary todrug treatment [125]. Regardless of the source, these ROS dam-age additional cellular components such as proteins and lipids[65,77], ultimately leading to energetic failure [125] and apopto-sis [126,218]. The result of these derangements include increasednociception as well as distal degeneration of intraepidermal nervefibers, as is seen in animal models of CIPN caused by paclitaxel [23].These data suggest that studies of CIPN must consider the distalmost aspect of axons, and not just proximal segments seen in thesciatic nerve or dorsal roots since damage is not uniform.

ROS and RNS are also a prominent component of HIV, and itstreatment-induced injury. The generation of these species appearsto be most harmful to the neuronal cell body [115]. Antioxidanttreatment improves cell survival but not neurite outgrowth [115],emphasizing the importance of ROS to somal, but not axonal, injury.Lehman and colleagues confirmed these observations in animalmodels of HIV infection, whereby the virus increased hydrogenperoxide production as well as oxidative and nitrosative proteinmodification in the sural, but not the sciatic, nerve [144]. The selec-tivity of sural nerve versus sciatic nerve may be due to the increasedsensitivity of distal sensory fibers to mitochondrial dysfunction, asdiscussed previously [144].

2.4. Intracellular and inflammatory signaling

In diabetes, in addition to non-enzymatic modification ofbiomolecules, AGEs are also bioactive as ligands for two majortypes of cell surface receptors. The first discovered receptor, recep-tor for AGE (RAGE), was identified through the selective bindingof glycosylated albumin to the surface of mouse macrophageswith subsequently AGE/RAGE internalization [260,262], leadingto macrophage proliferation in a granulocyte/macrophage colonystimulating factor (GM–CSF) dependent manner [292]. Since itsidentification, RAGE has been found to be expressed by a varietyof cell types, including neurons (as reviewed in [230]). Vlassaraet al., hypothesized that RAGE acts to clear harmful AGE modifiedproteins from the body [260]. Interestingly, the RAGE receptor alsohas a soluble isoform that is believed to be a scavenger receptor forAGEs and found in many tissues, including the adult nervous system[53]. A reduced level of this scavenger isoform is correlated withincreased risk of peripheral neuropathy in patients with type II dia-betes [13]. RAGE, however, is not simply a net to clear AGEs, but alsocan initiate an inflammatory response through cytokine release[289], including NF-�B mediated transcriptional activation of pro-inflammatory cytokines TNF-�, IL-1ß, and MCP-1 [289], a pattern ofcytokine expression that may facilitate tissue remodeling, as occursin atherosclerosis [263]. RAGE has been identified on endothe-lial cells [178,217], and neurons [32], in vivo, which suggests animmune response with the concomitant increase in ROS could beinitiated by AGEs in these tissues, thereby effecting additional vas-cular or neuronal injury [273]. In addition to tissue remodeling, thedownstream effect of the induction of these cytokines may be theproduction of ROS, as monocytes from patients with diabetes havegreater ROS production than control cells [79]. Cultured endothe-lial cells and AGE infused mice also demonstrate a RAGE dependent

increase in oxidative stress and NF-�B induction upon exposure toAGEs [285]. Indeed, the antioxidant �-lipoic acid protects Schwanncells from AGE induced apoptosis in vitro [219]. Thus, RAGE con-verts the transient inflammatory signal of the AGE into a sustainedinflammatory response that may lead to a long term inflammatorystate, thereby hindering treatment [25,79].

After the identification of RAGE, three other receptors wereidentified (AGE-R1, AGE- R2, and AGE-R3) as part of a large AGE-receptor complex [288,264], (as reviewed in [259]). As a complex,AGE- R1/R2/R3 has been shown to be up regulated in the presenceof AGEs with AGE-R3 demonstrating the greatest induction afterexposure, and AGE-R2 phosphorylation increased in vitro uponexposure of human umbilical vein endothelial cells to AGE-BSA[232]. Together, these data suggest that AGE-R1 may serve as astable receptor, while AGE-R2 effects the intracellular responsethrough AGE-R3 following AGE-R2 tyrosine phosphorylation. Therole of intracellular signaling by the AGE-R complex and the rel-evance of the previously identified activities of each componentin the larger complex remain to be elucidated. Interestingly, earlydata on the AGE-R complex suggests AGE binding leads to a IL-1 dependent late induction of progrowth cytokine insulin-likegrowth factor (IGF-1) in monocytes in vitro [137], linking RAGEcytokine release to AGE-R response.

It should be noted that much of the work on the AGE-Rs hasbeen performed in endothelial cells, reinforcing the importance ofvascular injury, with concomitant ischemia, in the developmentof neuropathy, as is seen with RAGE. Current models suggest adelicate balance between the pro-inflammatory and tissue remod-eling effects of RAGE and AGE clearance by the AGE-R complex[150], whereby AGE binding facilitates tissue remodeling andinflammatory cell recruitment, leading to vascular occlusion andneuronal/axonal injury. This model remains to be tested in vivo,however.

While the function of PARP in the regulation of metabolismthrough GAPDH modification and as an effector of ROS injurywas previously discussed, it is also responsible for the regula-tion of inflammatory signaling. PARP was elegantly demonstratedto, upon exposure to inflammatory particles like LPS and TNF-�,increase transcription factors that lead to an increased expressionof inflammatory cytokines and iNOS [112]. The expression of iNOSis particularly interesting, as its up regulation varied by cell typeand stimulus [112]. Nitric oxide can also initiate damage throughits radical as well as signal through in an independent cascade.

Nitric oxide serves as both a vasodilator and neurotransmit-ter that has a complex activity in neuronal signaling, damage, andrepair with mixed data describing its protection from or contribu-tion toward cellular damage and neuropathy (as reviewed in [306]).As described above, iNOS is induced in glia by PARP [113] where itserves an inflammatory function. However, in cultured endothe-lial cells, endothelial nitric oxide synthase (eNOS) has been shownto be down regulated in the setting of hyperglycemia, as a resultof O-linked N-acetylglucosamine modifications secondary to acti-vation of the hexosamine pathway, thereby increasing the risk ofatherosclerosis and/or microvascular ischemia [82]. Interestingly,an early study conflicted with the previous data and found NOSand TNF-� to be induced in endothelial cells upon exposure to gly-cated albumin [7]. The authors of this study postulated that theNOS and AGE balance is critical for early and late development ofdiabetic complications, where nitric oxide is increased early in thedisease through the activity of NOS, thereby damaging glomerulithrough hyperfiltration, whereas AGE products serve to quench NOin the vasculature later in disease, thereby reducing vasodilatorycapacity [7]. Thus, in the setting of hyperglycemia, reactive nitro-gen intermediates may be produced within the nervous system asa result of PARP activation secondary to ROS damage while, concur-rently, oxygen flow may be reduced through impaired mechanisms


of vasodilation. Together, the increase in iNOS and decrease in eNOSare two hits toward a toxic knockout of neurons and glia.

In addition to PARP and NOS signaling, neurotrophic factor sig-naling is also altered in diabetes. While all of the research discussedthus far has focused on the effect of hyperglycemia on nerve pathol-ogy, recent work has suggested that insulin, or the lack thereof,may also facilitate the development of the complications associ-ated with type I diabetes. Indeed, Sima et al., suggest differentnerve conduction properties between type I and type II diabetesmay be a result of the loss of insulin and C peptide that classi-cally occurs in type I diabetes [227]. C-peptide is derived from thesame prohormone as insulin and is increasingly recognized as hav-ing distinct, albeit complementary, effects to the action of insulin(as reviewed in [265]). C-peptide will be lost at the same time asinsulin, since they are both part of the same precursor peptide. Theimportance of the loss of C-peptide and insulin toward the devel-opment of the complications of diabetes was supported by morerecent experiments showing diabetic animals had a reduced abil-ity to up regulate neurotrophic factors (IGF-1, IGF-1 receptor, p75,and Trk A) in response to nerve crush injury, ultimately leadingto reduced regenerative ability and decreased nerve fiber density[190,196]. This deficiency was largely selective for type I, not typeII, diabetic models, suggesting that the deficiency of insulin andC-peptide, not hyperglycemia, leads to axonopathy and decreasednerve fiber density [196]. Evidence for the importance of insulinand C-peptide to the development of axonal defects in type I dia-betes comes from rescue experiments where exogenous C-peptideimproved conduction deficits, myelination defects, regenerativecapacity, and nerve fiber number [226].

Additional work has clarified the protective role of the insulininduced neurotrophic factor insulin-like growth factor 1 (IGF-1). Given a decrease an insulin, as is seen in type I diabetes,it is perhaps unsurprising that IGF expression is decreased inpatients with type I diabetes versus normoglycemic controls [190],Long appreciated for its anti-apoptotic activity in cancer andinjury (as reviewed in [256]), IGF-1 was recently found to pro-tect DRG neurons from hyperglycemia induced apoptotic signaling[145].

Other signaling axes have been identified to be dysregulatedin diabetes. Nerve growth factor (NGF) is well known to supportsensory fiber survival in vitro and in vivo [58–60,146,147] and wasrecently demonstrated to be transiently up regulated in the DRGs ofan animal model of type II diabetes during the onset of mechanicalallodynia, suggesting dysregulated NGF signaling may facilitate thedevelopment of one of the hallmarks of diabetic neuropathy – pain[54]. NGF levels may be elevated at the onset of injury [54], facilitat-ing the development of neuropathic pain, but then fall later in thecourse of the disease [93], thereby reducing regenerative capacity,although this pattern of expression may be dependent on the typeof diabetes.

Altered signaling to increase inflammation is a prominent com-ponent of CIPN. In animals models of paclitaxel toxicity, ATF3,a general, transient marker of neuronal injury [250], is up regu-lated in DRG neurons within a day of drug administration, whileglia increase expression of injury markers nearly a week after thefirst dose of the drug [195]. Additionally, markers of macrophage(CD68) and microglia (CD11b) activation increase one week fol-lowing treatment [195]. These data show an evolving pathologywhereby the DRG neurons are first harmed, then supportingglia in the DRG and nerve, which ultimately leads to recruit-ment or activation of inflammatory cells (macrophages, microglia)concomitant with symptom onset [194,195,272], and increasedexpression of many pro-inflammatory cytokines (as reviewed in[271]). Macrophage activation leads to matrix metalloproteinases-3 and -9 and, as a result, increased tissue degradation [182,225].Thus, the chemotherapeutic agents increase inflammation in the

nerve and ganglia, which may then lead to tissue damage and moresevere deficits.

Inflammatory signaling is a critical mechanism of HIV neu-ropathy. Indeed, both HIV proteins and systemic inflammationsecondary to the viral infection may damage neurons and axons (asreviewed in [133,251]). Recent work has shown gp120 induces sep-arate processes of injury in the neuronal soma versus the axon. In acompartmentalized culture of DRG neurons, gp120 reduces axonallength in an axon/Schwann cell only compartment and triggersapoptotic cell death when applied to the soma [165]. Interestingly,in the absence of Schwann cells, DRG soma were protected fromapoptosis, but axons were still sensitive to the application of gp120[165], suggesting different injury pathways were active in the twoareas. Ultimately, Melli et al. found that this response is due to selec-tive binding of gp120 to chemokine receptors on axons which leadsto caspase activation, and, thus, injury and degeneration [165]. Theengagement of apoptotic machinery in the soma, however, wasdistinct from the mechanisms in the axons as suggested by theSchwann cell dependence of soma apoptosis in response to gp120[165]. Additional work found gp120 binding to chemokine receptorCXCR4 on Schwann cells in the DRG to result in the release of theligand RANTES (regulated upon activation, normal T-cell expressedand secreted). RANTES then binds to a different chemokine recep-tor (CCR5) on the neuron, leading to release of TNF-� by neuronsand autocrine apoptotic signaling through its receptor and the c-Jun cascade [26,134]. The importance of CXCR4 and CCR5 to thedevelopment of HIV neuropathy also extends to the initiation ofinflammation [127]. VPR has been shown to evoke very similar,pro-inflammatory responses in DRG neurons [2]. In addition to theactivation of cell mediated inflammation, Apostolski, et al. showedgp120 may mediate DRG neuron cell death by activation of thecomplement cascade [11]. Thus, HIV may enter the peripheral ner-vous system through other cells, but its proteins and the immuneresponse may indirectly damage neuron cell bodies and axons,albeit through slightly different mechanisms.

In addition to the inflammation from the virus, recent work hasidentified antiretrovirals to also increase inflammatory signaling[303] and activation of apoptotic machinery [26]. To this end, ddCincreases expression of TNF- � in GFAP+ cells in the dorsal hornand neurons in the DRG [303]. In addition to TNF-�, BDNF has alsobeen shown to facilitate the development of mechanical and ther-mal hyperalgesia following treatment by a nucleoside analog byincreasing firing rates of dorsal horn neurons to stimuli [204]. Thisfinding suggests ddC increases BDNF release which ultimately leadsto enhanced synaptic connectivity between primary nociceptorsand dorsal horn neurons. Thus, in addition to the inflammatorysignaling from the virus itself, the antiretrovirals may also initi-ate damage through modulation of the inflammatory response viaTNF-� and synaptic connectivity via BDNF.

Aberrant inflammatory signaling is the primary pathogenicmechanism of HCV neuropathy. As discussed previously, whilecryoglobulinemia is not necessary for the development of periph-eral neuropathy, it changes the symptom constellation from alocalized neuropathy to a more generalized disorder affectingmultiple nerves. Cryoglobulinemia has long been appreciated toprecipitate peripheral neuropathy [48]. Sural nerve histology of apatient with cryoglobulinemia showed small and medium vesselperivascular inflammation with some vessels completely occludedand myelin degeneration [48]. IgM and IgG were found depositedon smaller vessels, while fibrinogen was readily stained on thelarger vessels [48]. The authors of this report suggest the patient’sneuropathy was precipitated by the cryoglobulinemia, wherebyIgGs bound to myelin, leading to direct immune attack, as wellas to the small and medium vessels, leading to vascular occlusionand ischemia. A different study found that the antibodies bind-ing to myelin were largely against myelin associated glycoprotein


(MAG) [244]. Thus, the IgG and IgM antibodies may cause damagethrough two mechanisms: activation of complement on myelin andischemia by precipitation of immune complexes and lymphocyticinflammation within the vasa nervorum, causing luminal narrow-ing or occlusion [29,244]. While these mechanisms may explain theneuropathy in patients with HCV and cryoglobulinemia, recall that30–70% of patients with HCV neuropathy may not have cryoglob-ulins. In these patients a different mechanism must be responsiblefor their symptoms.

Interferon-� (IFN- �) modulates the development of peripheralneuropathy in patients infected with HCV. Both IFN-� and IFN- �are cytokines that are released during viral infection to induce an“antiviral”, intracellular state. IFN- � can be induced by most cells,while IFN-� is specifically released by lymphocytes as part of thecell mediated immune response (as reviewed in [92]). In additionto endogenous induction of IFN-� by HCV, given its general antivi-ral activity, exogenous IFN-� has become a critical componentof combination therapy for certain HCV infections (as extensivelyreviewed in [222]). Interestingly, autoimmunity increases follow-ing IFN-� monotreatment in HCV infection [88], despite a decreasein cryoglobulins and viral titer. This suggests that IFN-� producesa pro-inflammatory state that may facilitate damage to the vasanevorum and myelin. Thus, it is a fine balance between inflam-mation to clear the virus and autoimmunity. This autoimmunitylikely initiates the development of neuropathy in HCV; there isa combination of ischemia due to occluded small vessels anddirect attack against the myelin. This model is consistent withthe non-dependence of neuropathy on the presence of cryoglobu-lins. While the cryoglobulins may increase vascular inflammation,leading to ischemia and more widespread neuropathy, anti-myelinproteins may still be present in the absence of cryoglobulins, soneuropathy may still develop. It is still unclear how ribavirin mayreduce the incidence of neuropathy, but one possibility is by lead-ing to more complete viral clearance, ribavirin reduces systemicinflammation, including cryoglobulins and anti-MAG antibodies.By reducing these compounds, IFN-� autoimmunity, and, thus,neuropathy, is less likely to develop. This hypothesis remains to betested.

2.5. Axonal transport defects

Diabetes also affects axonal health by modulation of axonaltransport. Nearly 30 years ago, Medori et al. identified impairedslow axonal transport of cytoskeletal proteins neurofilament (lightand medium subunits), tubulin, and actin in an animal model oftype I diabetes versus healthy controls [164]. The authors alsoobserved increased axonal cross sectional area in the proximalaspect of the axon, but a reduced area in the distal aspect. Theyhypothesized that this pattern may be a result of reduced accu-mulation of cytoskeletal elements distally because of impairedtransport [164]. Additional cytoskeletal protein defects includedirect actin and neurofilament glycation in the setting of hyper-glycemia in vitro [34], and in vivo [69,191] (as reviewed in [163]),as well as reduced expression of heavy and light neurofilament, and�-tubulin in the DRGs of type I diabetic animals [172]. It shouldbe noted, however, that while actin glycation does not interferewith its ability to polymerize [191], glycosylated tubulin has areduced polymerization ability [274]. The expression and modifica-tion of these cytoskeletal proteins (actin, neurofilament, tubulin) isbelieved to interfere with cytoskeletal assembly, and, thus, axonaltransport [163]. RAGE is predicted to interact with actin throughits effector mDia1 [124,129,157], but recent work has elegantlyshown that slowed axonal transport in diabetic animals is inde-pendent of RAGE expression [129]. Despite the slowed transportof the RAGE/actin effector protein mDia1 in diabetic animals (wildtype and RAGE knockout), RAGE itself was not differentially present

between diabetic and control animals. While the exact mechanismsof slowed axonal transport in diabetes, and how it may effect othercellular processes, remains to be elucidated, one can imagine thatsuch large scale changes in the cell may alter its ability to respondto its environment, perhaps making it more susceptible to damagethrough other mechanisms or less efficient with cellular repair andregeneration.

Microtubule defects with the concomitant transport difficul-ties is a critical component of paclitaxel-induced CIPN with muchwork focusing on how microtubule stabilization by taxanes, inparticular, may interfere with axonal transport (as reviewed in[106]). Incubation of DRG neurons with high levels of paclitaxel hasbeen shown to interfere with anterograde transport of HRP [243].Interestingly, while paclitaxel binds to the lumen of microtubulesand, thus, cannot directly hinder motor movement [106], electronmicroscopy shows decreased rates of microtubule crosslinks andreduced density of the crosslinking microtubule associated pro-teins upon DRG neuron exposure to paclitaxel in vitro [243]. Thedearth of these crosslinks could alter transport dynamics. Alterna-tively, increased microtubule density and aggregation [46,106,243]may hinder motor movement. However, these microtubule abnor-malities have not been observed in patient sural nerve biopsies[211], perhaps due to lower drug concentrations.

An alternative hypothesis of transport interference in paclitaxelmediated CIPN is covalent modification of tubulin interfering withmolecular motor function. As a microtubule polymerizes, the tubu-lin components that are not on the elongating end can be acetylated,glutamated, and detyrosinated to increase stability (as reviewed in[106]). Investigations of dendrite/axon identity have found tubulindetyrosination to organize distribution and movement of kinesinalong the axon [83,139]. Paclitaxel enhances all three posttrans-lational modifications, thereby disrupting axon/soma/dendritepolarity [117,276]. The role of posttranslational modification iscomplex, however, as each modification can alter motor bindingand motility [106], and different motor subtypes may bind to differ-ent modified tubulins preferentially [41]. Nonetheless, interruptionof transport may lead to poor anterograde transport of vesiclesand organelles, as well as retrograde transport of trophic factors[106]. Transport dynamics may also be affected at the end of theaxon, where motors must release from and reattach to differentmicrotubules. Indeed, a recent paper has shown that in a drosophilamodel of a degenerative motor neuron disease with a tubulin bind-ing domain mutation in a subunit of dynein, dynein accumulatesin the terminal bouton because of a failure to bind to the end ofthe microtubule [149]. The microtubule end and motor dynamicsare critical for maintaining proper and equitable delivery of vesi-cles to terminal boutons [277]. This model suggests dysfunctionof transport could lead to derangements at the axon terminal and,thus, interfere with communication or organelle delivery and leadto terminal degeneration, although this hypothesis has not beentested.

Surprisingly, low dose paclitaxel has been shown to facilitateregeneration, rather than degeneration, in the central nervous sys-tem [120]. The authors of this initial study suggested paclitaxelmay facilitate regeneration by reducing scarring [120]. An addi-tional hypothesis was proposed three years prior to the discoveryof the regenerative benefit of low dose paclitaxel. Witte et al.suggested that since paclitaxel modifies neuron polarity to cre-ate multiple axons from one cell, perhaps low dose paclitaxel maybe helpful to “convert a nongrowing minor neurite into a growingaxon” to facilitate central nervous system regeneration [276]. Thus,the microtubule stabilizing dynamics must be delicately balancedbetween stable and unstable, polymer and monomer, such thatpaclitaxel may either cause axonal degeneration through interrup-tion of axonal transport or regeneration by stabilization of growingneurites.


Axonal transport defects are also observed in CIPN caused by cis-platin and bortezomib. As with paclitaxel, in a model of bortezomibCIPN, tubulin polymerization is increased in vivo and in vitro uponclinically appropriate drug concentration [167]. The exact mecha-nism of bortezomib tubulin stabilization remains to be elucidated.In addition to bortezomib and paclitaxel, early studies on cisplatinneurotoxicity showed impaired anterograde and retrograde fasttransport in vitro with no gross morphologic abnormalities [210].The authors of this study suggested cisplatin may be directly toxicto kinesin and dynein through crosslinking or motor ATPase inhi-bition [210], although little work has been pursued in this line ofresearch.

2.6. Channelopathy

While diabetes does have some sodium/potassium channel dys-function [107], as discussed with respect to metabolic deregulationand conduction velocity, the details of direct channel modulationin diabetes is still unclear [254]. However, channel defects are someof the fundamental dysfunctions in CIPN and GBS.

In CIPN, channel toxicity is especially relevant for plat-inum compounds and proteasome inhibitors. Of the platinumchemotherapeutics, oxaliplatin has the largest effect on channels.Indeed, recall that oxaliplatin has two types of neuropathy: an acuteas well as a more chronic form [22]. Thus far, the chronic neuropa-thy with numbness and functional impairment has been discussed.However, the acute neuropathy is characterized by transient coldhypersensitivity and parasthesias, which generally resolve on theirown and do not require dose changes [22]. Acute abnormalitiesof nerve, hippocampal neurons, and DRG neurons are observedin vitro after just 45 min of oxaliplatin exposure, where sodiumcurrent is drastically increased to produce larger compound actionpotentials in response to depolarization [4]. These abnormalitieswere abrogated with a sodium channel blocker, suggesting modi-fication of these channels likely contribute to the abnormality [4],and the increased refractory period of the neuron suggested thatit was the modification of the voltage gated ion channel inacti-vation, in particular, that was altered by exposure to oxaliplatin[4], with no effect on potassium channels [33]. The mechanismsof specific sodium channel sensitization remain to be elucidated,however, and a general increase in sodium current does not explainthe specific cold hypersensitivity observed in oxaliplatin CIPN.

Cold hypersensitivity is instead most likely due to oxaliplatintriggered sensitivity in TRP channels, including the capsaicin recep-tor (TRPV1) and “cold” receptors (TRPA1 or TRPM8) [8]. Whileoxaliplatin fails to directly modulate these receptors, cAMP rapidlyincreases in concentration upon drug exposure, suggesting cAMP isa second messenger to a signaling cascade initiated by oxaliplatinthat leads to TRP channel modification [8]. Additionally, Descoeuret al. identified two potassium channels, TREK1 and TRAAK, tobe drastically reduced in expression, while the expression of twodepolarizing channels, the sodium channel and hyperpolarizationactivated channel (HCN), were slightly elevated [75]. These changesappeared to specific for cold sensing neurons [75]. Thus, oxaliplatintreatment causes a global change in ion channel expression thatleads to a higher membrane potential and, thus, more robust firingof TRP channels. Additionally, modeling experiments by Dimitrovet al. have suggested [78] that the reduction in potassium currentin internodal regions of myelinated axons could lead to the nervefiber defects first observed by Adelsberger et al. [4], with actionpotential trains, and thus a stronger central response following asmall peripheral stimulus.

In addition to cisplatin, bortezomib has also been shown tointerfere with ion channels. In a recent animal study with bothacute (single dose) and chronic (multiple dose) administrationof bortezomib, the authors found mechanical hyperalgesia and

an increase in protein levels of TRPV1 in DRGs and spinal cord[201]. Interestingly, the transcript levels of TRPV1 and CGRPwere reduced in these tissues, suggesting the protein levels likelyincrease because of bortezomib’s inhibition of the proteasome[201], thereby potentially increasing neuronal response to noci-ceptive stimuli. Additionally, patients treated with bortezomibhad increased resting membrane potential, which would leadto increased neuronal response for a given input. This changein potential preceded axonal degeneration [176]. Degenerationwas suggested by the authors to be due to energetic collapsein the axon, from mitochondrial dysfunction leading to impairedNa+/K + ATPase activity and, thus, intraaxonal accumulation ofsodium ions [176] and increased calcium influx by reversal of thesodium/calcium exchanger [233]. This influx of calcium may beginthe path to apoptosis. This hypothesis remains to be tested, how-ever. Nonetheless, channel dysfunction and changes in membranepolarization appear to be a critical mechanism for the developmentof hyperexcitability and acute symptoms of CIPN, especially fromplatinum chemotherapeutics and proteasome inhibitors.

While little work has examined the electrophysiological effectof HIV or its proteins on DRGs, there do appear to be some subtlechanges. Chiefly, both gp120 [188] and Vpr [2] have been shownto increased DRG neuron excitability, perhaps through the influxof calcium following activation of the chemokine receptors. Inmacrophages, gp120 binding to chemokine receptors has beenshown to directly regulate calcium, potassium, and chloride trans-port [148].

While channel dysfunction has not been identified as apathogenic mechanism in HCV neuropathy, the node of Ranvieris the primary insult in GBS. Much work by Yuki and others haveshown molecular mimicry between C. jejuni antigens and ganglio-sides results in immune attack of the node of Ranvier. The firstclues to the pathophysiology were the association of anti-GM1 gan-glioside antibodies with the AMAN form of GBS following C. jejuniinfection [121,296]. The presence of these antibodies predicted areversible conduction block, believed to be due to disruption ofthe node of Ranvier [138,141]. The deposition of these antibodiesleads to complement deposition on the axolemma [114] and, thus,disruption of axons/Schwann cell architecture at the node and para-nodal regions [43], ultimately leading to disruption of ion channelorganization at the node of Ranvier [235]. More specifically, anti-body deposition and complement activation increases potassiumcurrent in the paranodal region and decreases sodium current inthe node, thereby leading to conduction failure [239]. While thismay be the mechanism of block, it does not link C. jejuni to thedevelopment of autoantibodies.

A key breakthrough in the understanding of the pathophys-iological link between C. jejuni and GBS came from Yuki andcolleagues when they found rabbits that were inoculated with GM1ganglioside developed the axonal phenotype of GBS [295]. In afollow up study using this in vivo model, Yuki, et al. found thelipooligosaccharide of C. jejuni to be sufficient to induce anti-GM1antibodies and paralysis consistent with GBS, and that the anti-GM1 antibodies were sufficient to induce the symptoms [294]. Thefindings suggest GBS is the result of molecular mimicry betweenC. jejuni antigens and host gangliosides [294]. Much like Koch’spostulates for infectious organisms, Ang, Jacobs, and Laman pro-posed a number of criteria to define molecular mimicry betweenpathogen antigens and host tissue as a cause of autoimmune dis-ease [10]. These include 1. Epidemiological association betweenpathogen and disease, 2. Identification of antibodies against selfantigens, 3. Identification of the pathogen’s antigen that elicits theself antibodies, and 4. Recapitulation of the disease in an animalmodel [10]. C. jejuni and GBS successfully filled all criteria and isthus considered to be a genuine example of molecular mimicrybetween a pathogen and host molecular that leads to an autoim-


mune disease [10] . After the identification of the C. jejuni/GM1relationship, other pathogen/antigen links were identified for GBS,including anti-GD1a ganglioside [122], anti-neurofascin [76,200] aswell as antibodies against other nodal/paranodal proteins includinggliomedin and contactin [76]. The motor selectivity of the AMANsubtype of GBS may be due to differential ganglioside expressionbetween motor and sensory axons and myelin [186], with GM1found mainly in motor myelin [187]. However, these results werechallenged in a later, larger study [237], suggesting more work isneeded to separate the ganglioside composition of both motor andsensory axons and myelin in both healthy controls and patientswho develop GBS. Nonetheless, anti- ganglioside antibodies thatinterfere with the node of Ranvier appear to be common in manyof the sensory and motor subtypes of GBS, with specific gangliosidetargets being more prevalent in certain subtypes [236].

Thus, a variety of diseases and neuropathies are caused by only afew mechanisms: mitochondrial dysfunction and ROS, altered sig-naling and inflammation, and finally reduced axonal transport andchannel dysfunction. While these pathophysiological mechanismsinevitably will be valuable for therapeutic design, recent advancesinto the downstream effectors of degeneration reveal fundamentalmechanisms of axonal degeneration and promise to be essential forthe development of treatments that may be applied universally todegeneration caused by disease as well as trauma.

3. New insights into mechanisms of degeneration

Wallerian degeneration is the process whereby an injured axondegrades and debris is cleared to facilitate axonal regeneration andrecovery. Axonal degeneration is not a passive process like a wirebeing broken, however. Rather, it is an active process that requiresaxon to soma signaling. This type of self destructive pathway isreminiscent of apoptosis, but the pathways of axonal degenera-tion have been shown to be independent of caspases and apoptoticsignaling [97]. One can imagine this signaling may be through anactive “injury” signal or the loss of a “survival” signal. Early studiessuggested axonal degeneration is a result of the former case. Afteraxotomy, there is a delayed influx of calcium with subsequent acti-vation of the calcium activated protease calpain and other proteasesthat is necessary and sufficient for axon degeneration and digestionof the cytoskeleton [103,153,286]. Interestingly, inhibition of cal-pain does delay Wallerian degeneration, but chelation has a muchmore robust effect, suggesting the influx of calcium likely has multi-ple roles, in addition to the activation of calpain [297]. This calciuminflux marks a late step toward axonal degeneration (once proteinsbegin to be degraded, the process cannot be reversed), suggestingit is the result of up stream signaling, but what is this signal, andwhat are the components of this pathway?

A curious inbred mouse strain was reported to have delayedWallerian degeneration where the axons in a transected nerveremained largely intact three days after injury, a time pointwhere robust degeneration normally has begun [151]. Later studiesidentified the mutant gene responsible for this slowed Walle-rian degeneration, WldS, [152,193] as a fusion of ubiquitinationfactor E4B (Ube4b) and nicotinamide mononucleotide adenylyl-transferase (Nmnat). The fusion protein is chiefly found in thenucleus of these animals [154], although its protective activitydepends on its activity in the axon [57,214]. The Ube4b:Nmnatfusion results in increased stability of Nmnat versus wild typeNmnat [105]. Studies in mice and drosophila have shown that theaxon protective effects of the WldS gene product requires the activ-ity of Nmnat [16,215], while the Ube4b fusion allows the WldS

gene product to bind to another protein, which may localize theprotein fusion to the axon or mitochondria and/or allow it to inter-act with additional, unknown proteins [16]. While Nmnat appears

to be critical for axonal protection [16,216,298], the classic prod-uct of Nmnat reactions, NAD, is not required intracellularly forresistance to degeneration [216], despite protection from degener-ation with exogenous, extracellular NAD application in vitro [267].These data suggest that both extracellular NAD and preservedNmnat function protect axons from degeneration but through twodistinct mechanisms [216,298]. The secondary activity of Nmnatmay be chaperone activity [299] or regulation of mitochondrialmetabolism [283]. Nmnat has been shown to be active within themitochondria. Several studies have shown Nmnat to reduce cal-cium spikes after axotomy [3,15], which ties the early stages ofaxonal degradation signaling to the later calcium dependent phasediscussed above. Additionally, the WldS gene product has beenshown to modulate energy metabolism within the axon to main-tain ATP levels following injury [221] as well as to reduce ROSproduction [184,199].

This arrangement of the pathway suggests that, in contrast to thelate injury signal of calcium, Nmnat may produce a survival signalthat is lost during axonal injury. Indeed, when the MPTP is activatedin WldS mice, axons degenerate, which confirms the upstream posi-tion of Nmnat to calcium signaling [21]. If Nmnat is transportedthroughout the axon [105], reduced transport may increase dis-tal axon sensitivity to degeneration due to reduced Nmnat levels,tying this mechanism to the axonal transport defect pathways.Additionally, E3 ligases have been shown to balance degenerationand regeneration, where increased activity of an E3 ligase reducesNmnat expression, thereby initiating degeneration [18,281], whileinhibition of the proteasome system resists Wallerian degeneration[297]. Thus, Nmnat likely acts as a survival signal that is activelydistributed throughout the axon. Once an axon is injured, Nmnatlevels decrease, ultimately leading to calcium influx and activationof calcium dependent proteases and degradation of the axon (asreviewed in [61]). WldS interferes with this process by resistingdecreases in NMNAT concentration.

A loss of function mutation of a component of Toll-like recep-tor signaling has been found to phenocopy the gain of function ofthe WldS gene product, presenting an additional therapeutic targetfor protection from axon degeneration. A member of the Toll-likereceptor (TLR) adaptor family, SARM/MyD88-5, was first identi-fied to negatively regulate TLR signaling [44] and to be expressedin vivo in neuronal mitochondria and microtubules where it asso-ciates with JNK3 in vitro [136], a pathway known to be critical foraxon degeneration [223]. SARM null mice are resistant to cell deathfollowing oxygen and glucose deprivation, suggesting SARM, likeNmnat, may be critical for neuron degeneration and death signal-ing [136]. These findings were extended to axon degeneration morespecifically, where SARM loss of function resulted in resistanceto axon degeneration following axon transection [189] and with-drawal of trophic support in vitro [104]. SARM may also be activatedby CaM kinase, linking this pathway to the calcium influx char-acteristic of axonal degeneration [189]. It is likely that SARM is acommon pathway toward axon degeneration from various insults,as is the case with the downstream JNK signaling, which may beactivated by SARM or by an additional emerging pathway involv-ing dual leucine kinase (DLK) [170]. Thus, the axon degenerationpathway appears to contain many points of convergence such thatmany different types of insults may result in initiation of a commondegradation pathway.

These data suggest a model of the active process of axondegradation. The balance of proteasomal degradation and activetransport maintain Nmnat expression at a constant, steady statelevel. In the setting of an injury, either one of these processesmay be affected such that Nmnat levels fall below a threshold. Thedecrease in Nmnat then triggers calcium influx and release frommitochondria, which activates calpain. Alternatively, calpain maybe activated by SARM (which is itself stimulated by injury) with JNK


Fig. 2. Summary of the mechanisms of peripheral nerve degeneration. (For interpretation of the references to colour in this figure legend, the reader is referred to the webversion of this article.)Peripheral neuropathy in a wide range of disease, including diabetes, CIPN, viral infections, and GBS, develops as a result of the interaction of various combinations of justsix processes: altered metabolism, covalent modification, impaired organelle function with ROS/RNS, altered signaling, slowed axonal transport, and altered ion channeldynamics. The figure delineates which process is active in which disease by color, as shown in the key. All of these processes interact to ultimately converge on the neuronaldeath and/or axonal degeneration pathways, with the major interactions outlined in the above figure. The different black, dark gray, and light gray coloring of the arrows isfor clarity only.

signaling. Calpain then leads to protein degradation. Additionally,DLK may activate JNK in parallel to Nmnat loss or act to signal a dif-ferent type of insult. Clearly, the details of the axonal degenerationprocess continue to be elucidated and much work must be done toclarify how WldS (Nmnat), SARM, and DLK converge or diverge. Anyinsult that activates this pathway or modulates any of the compo-nents, as in mitochondrial dysfunction or slowed axonal transport,will lead to axonal degeneration, as is seen in diabetes, CIPN, HIVneuropathy, HCV neuropathy, and GBS (Fig. 2). Interestingly, Nmnathas been shown to be regulated by PKC and to modulate PARP,which links Nmnat activity to two additional points of injury inneuropathy, as discussed above [24].

4. Conclusion

While a variety of insults, including diabetes, chemotherapy,HIV, HCV, and C. jejuni may lead to peripheral neuropathy, thereare only a handful of mechanisms that cause it. These includealtered metabolism, covalent modification of proteins, reducedorganelle efficiency with concomitant increases in ROS and RNSproduction, altered intracellular signaling (e.g. PKC, RAGE) andincreased inflammation, reduced axonal transport, and modulationof ion channel expression and/or dynamics (Fig. 2). Alterations inmetabolism, as seen in diabetes, may modulate the flux through dif-ferent metabolic pathways with concomitant changes in reactivemetabolites. Many of these mechanisms are intrinsically linked,such as slowed mitochondrial transport exacerbating the accumu-lation of mitochondrial mutations during the normal aging process,or the increase in ROS associated with mitochondrial dysfunc-tion.

Downstream of the damage from the pathophysiological pro-cesses, in a paradigm reminiscent of apoptosis, degeneration occursin an early, non-committed (“survival”) and late (“death”) stage of

degeneration marked by the increase in calcium and protease acti-vation. While the details of this processes are still being elucidated,current data suggest that within the axon, Nmnat acts as a survivalsignal that decreases during axonal injury. This fall leads to the initi-ation of the degeneration pathway. While the mechanism wherebyNmnat modulates downstream effectors such as calcium is stillbeing investigated, its potential role in mitochondrial metabolismis particularly interesting, given the importance of this organelleto the generation of neuropathy through many diseases. The mul-tipurpose role of Nmnat in NAD metabolism, chaperone activity,and mitochondrial function regulation suggests that it may protectdifferent pathologies in a variety of ways, with one modality notbeing protective for all diseases (as proposed in [64] and observedin transection versus Charcot–Marie–Tooth disease [169]). Clearly,the protective effect of the WldS transgene is multifaceted and onlynow starting to be understood.

The promise of the WldS and SARM models of resistanceof axonal degeneration in the generation of pan-disease neuro-protectants is reflected in the many experiments showing theWldS gene to protect against neuropathy in a variety of dis-eases, including models of spinocerebellar ataxia [299], CIPN[268,269], diabetes [278,304], myelinopathy [212], progressivemotor neuronopathy [94], Charcot–Marie–Tooth disease [169],traumatic axon injury [169,266], and spinal muscular atrophy[169]. However, the WldS gene does not cure all deficits ofthese diseases. Indeed, WldS does not protect against diseaseonset or synapse abnormalities in the model of spinal muscularatrophy [169], and it loses its effectiveness in protection fromdegeneration with advanced age [192]. While research contin-ues to uncover the axonal degeneration pathway, the initiatingapparatus of this pathway and how it interacts with other path-ways (i.e., DLK) or components (e.g., SARM) have still not beenuncovered.


Clearly, while there are many new exciting avenues of researchinto the unifying mechanisms of neuropathy, and how modulationof these mechanisms may help treat or prevent neuropathy, there isstill much work that needs to be done in understanding how axonsbecome more susceptible to injury and degeneration with age, aswell as what, if any, commonality there is between the pathwaysof development, degeneration, and regeneration (Fig. 2).

Acknowledgements

This work was supported by the Dr. Miriam and Sheldon G. Adel-son Medical Research Foundation, NINDS (R01 NS-43991), and theFoundation for Peripheral Neuropathy. The authors wish to thankCatherine Kiefe for her artistic talents and expertise in the produc-tion of figure two.

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