Myelin biology and disorders

References

Veterinary Neuropathology – Vandevelde et al 2012, Chapter 8

https://vet.uga.edu/ivcvm/courses/VPAT5316/02_neuropath/

Chris ThomsonBVSc(Hons), Dip ACVIM (Neurol), Dip ECVN, PhD Associate Professor Neurobiology,Dept. of Vet. Med.,University of Alaska, Fairbanks,Alaska.

Oligodendroglia

Cultured oligodendroglia in absence of axonshttp://www.med.keio.ac.jp

https://www.best.edu.au/

Myelinating spinal cord culturesGreen – myelin protein (PLP-DM20)Red – axons (phosphorylated neurofilament

http://stevegallik.org/sites/histologyolm.stevegallik.org

http://library.med.utah.edu/WebPath

PNS

http://science.sciencemag.org/content/sci/304/5671/F1.medium.gif

Node, Paranode Internode

LS nerve, thin sectionArrowhead – nodeArrow – Schmidt-Lantermann incisures

Myelinated and non-myelinated axons

http://vanat.cvm.umn.edu/neurHistAtls/pages/cns7.html

CNS EM image

Disorders of myelin

• Hypomyelination• Normal molecular composition, but reduced amount

• Dysmyelination• abnormal molecular composition, reduced amount and

abnormal morphology

• Demyelination• Primary – immune mediated attack on myelin• Secondary – to axonal loss (Wallerian (PNS) wallerian-like

(CNS) degeneration

• Myelinolysis• Leukodystrophy

• e.g. Rapid correction of marked hyponatraemia

Myelin loss and remyelination

• Effect of myelin loss • Slowed conduction or conduction block

• Axonal damage

• Remyelination

http://www.mayo.edu

www.thepageantplace.netHuman brainstem, LFB-CV stainMultiple sclerosis plaques

Duncan and Griffiths:J Neuropath & Expt Neurology1981, 40, 303

https://www.youtube.com/watch?v=LfGlTVYhDFI

Human diseases:• Pelizaeus-Merzbacher• Spastic paraplegia

Pathology – shaking pupsNormal spinal cord

Griffiths et al, J Neurol Sc, 1981; Griffiths et al, Neurocytology, 1981

Myelin chemistry

https://www.cell.com/cms/attachment/614389/4944411/gr2.jpg

Plp gene missense mutations

http://www.em.mpg.de/index.php?id=232&no_cache=1

D20 spinal cord, normal (wild-type) and jimpy mouseYool et al, Human Molec Genetics, 2000

Plp-Dm20 gene missense mutations

https://slideplayer.com/slide/8690166/26/images/12/MUTATIONS+IN+PLP+GENE+CAUSING+HYPOMYELINATION+IN+CNS.jpg

Mouse mutants

• Jimpy, rumpshaker, shiverer

Veterinary disorders of myelin• Primary

• Disease directly damages myelin, axons are normal• Hypomyelination, dysmyelination

• Onset 2-8 weeks, • Generalised body tremor, decreased at rest• Proprioceptive deficits possible• May improve with time (delayed myelination)

• except Springer Spaniels and Samoyeds

• Shaking pup (Springer Spaniel), Chow Chow, Bernese mountain dog, Dalmation, Samoyed, Weimeraner

• Congenital tremor calves, lambs, piglets• Congenital hypothyroidism

• rat terriers, Pettigrew 2007

• Demyelination • Progressive• Rottweiler, (Rabbits, Afghan hounds, miniature poodles,

Charolais cattle • Leukodystrophy (myelinolytic dz)

• e.g. globoid cell LD, galactocerebroside deficiency• Hyponatraemia with rapid correction• Hound ataxia – fed rumen meat, methionine deficiency

• Leukoencephalomyelopathy –• Rottweiler and Leonberger

• Virus induced – distemper, visna, CAE,

Fig 8-10, Vandevelde, leukoencephalomyelopathy Leonberger

• Secondary• dz damages axons, with secondary myelin loss

• Wallerian (axonal trauma), Wallerian like degeneration (axonal degeneration)

• Degenerative myelopathy – dogs, • gene mutations in some animals (SOD, α-tocopherol

transferase)

• Axonopathy, neuroaxonal dystrophy • dogs, cats, horses, sheep, cattle

• Storage disease – neuronal +/- oligodendroglial storage • GM(1) gangliosidoses

• Toxins (e.g. organoP, fungal)

• K9 distemper virus demyelinating leukoencephalitis• Primary, secondary or both?

• PNS• Hereditary – G. Ret and Tibetan mastiffs • Inflammatory demyelinating neuropathy

• (Guillain-Barre syndrome in people – immune mediated)

• LMN signs (paresis, decreased tone and reflexes)

Horse, cervical stenotic myelopathy

https://vet.uga.edu/ivcvm/courses/VPAT5316/02_neuropath/

Veterinary disorders of myelin

Myelin markers in CSF

• GSD with degenerative radiculo-myelopathy

• Disease primarily affects neurons

• Significant increase MBP (ELISA) in GSD with CDRM

• Oji et al, Vet Clin path, 2007, 3, 281-284