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Page 1: news and views - Denver, · PDF fileQQQQQQ P P QQQQQQ P P Ac QQQQQQ QQQQQQ QQQQQQ QQQQQQ QQQQQQ P P QQQQQQ P P Ac Ac Ac QQQQQQ P P Ac Ac QQQQQQ P QQQQQQ P QQQQQQ P P QQQQQQ P P Neuron

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32 volume 16 | number 1 | january 2010 nature medicine

(2008).7. Danilova, N., Sakamoto, K.M. & Lin, S. Blood 112,

5228–5237 (2008).8. McGowan, K.A. et al. Nat. Genet. 40, 963–970

(2008).9. Gazda, H.T. & Sieff, C.A. Br. J. Haematol. 135, 149–

157 (2006).10. Liu, Y. et al. Cell Stem Cell 4, 37–48 (2009).11. Akala, O.O. et al. Nature 453, 228–232 (2008).12. Gangaraju, V.K. & Lin, H. Nat. Rev. Mol. Cell Biol. 10,

116–125 (2009).13. List, A. et al. N. Engl. J. Med. 355, 1456–1465

(2006).14. Jadersten, M. et al. Haematologica 94, 1762–1766

(2009).

in immunodeficient mice. The basis for this proliferative advantage and the basis for the progressive nature of this disease remain to be determined.

1. Rollison, D.E. et al. Blood 122, 45 (2008).2. Barlow, J. et al. Nat. Med. 16, 59–66 (2010).3. Starczynowski, D.T. et al. Nat. Med. 16, 49–58

(2010).4. Van den Berghe, H. et al. Nature 251, 437–438

(1974).5. Ebert, B.L. et al. Nature 451, 335–339 (2008).6. Pellagatti, A. et al. Br. J. Haematol. 142, 57–64

Nonetheless, the number of patients stud-ied was small, and thus it is not clear how common an event this may be14. One issue not resolved by these two studies, though, is the basis for the clonal nature of 5q– MDS, as neither miR-145, miR-146a nor Rps14 has been shown to be a tumor suppressor protein. A fundamental paradox is that the MDS clones can take over the marrow space of an individual with this disease, yet it is very difficult to grow MDS cells in vitro or

Huntington’s disease is an autosomal domi-nant disease that affects about one in 10,000 people1. It commonly presents in adult life with personality changes, cognitive disturbances and abnormal movements. Huntington’s disease remains a fatal condi-tion, as there are no effective treatments to cure it or slow its progression.

Huntington’s disease is caused by an expansion of the polyglutamine-coding CAG trinucleotide repeat in the gene encoding huntingtin. The CAG repeat occurs within the coding region of the gene, and the mutant huntingtin protein abnormally accumulates in the brain in the form of inclusions that contain the mutant molecule plus a series of other proteins. The accumulation and aggre-gation of misfolded proteins is a pathological hallmark not only of Huntington’s disease but also of most age-related neurodegenera-tive disorders.

There is substantial evidence to sug-gest that the levels of mutant huntingtin strongly correlate with severity of the dis-ease phenotypes2,3. Accumulation of mutant huntingtin presumably leads to alterations in multiple cellular pathways such as gene transcription, energy metabolism, axonal transport, synaptic transmission and vesicle release4. Although it remains unclear which

of these mechanisms has the most impact on Huntington’s disease pathogenesis, it is well established that the abundance of mutant huntingtin is a major predictor of degenera-tion. This has been best shown in a transgenic

mouse model of the disease in which elimina-tion of mutant huntingtin expression resulted in reversal of the pathology2. Therapeutic benefit in Huntington’s disease may there-fore come from the selective clearance

Huntington’s disease: tagged for clearanceDimitri Krainc

The neuronal accumulation of mutant huntingtin is a hallmark of Huntington’s disease. New research shows that post-translational modifications of the mutant protein promote its clearance, uncovering new therapeutic targets for this disorder.

Dimitri Krainc is in the Department of Neurology,

Massachusetts General Hospital, Harvard

Medical School, Mass General Institute for

Neurodegeneration, Charlestown, Massachusetts,

USA.

e-mail: [email protected]

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Nuclear inclusions

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Mutant huntingtin

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Figure 1 Post-translational modifications of mutant huntingtin target it for degradation. Inhibitor of κB kinase (IKK)-mediated phosphorylation (P) of the amino terminus of huntingtin targets mutant huntingtin into the nucleus, where it interferes with gene transcription. Its acetylation (Ac) by cyclic AMP response element–binding protein (CREB)-binding protein (CBP) facilitates trafficking of mutant huntingtin into autophagosomes for degradation. Mutant huntingtin that is not cleared accumulates in the nucleus and cytoplasm in the form of inclusions. Increasing phosphorylation or acetylation of mutant huntingtin improves clearance of the mutant protein and reduces neuronal toxicity. ‘Q’s indicate glutamine residues.

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Page 2: news and views - Denver, · PDF fileQQQQQQ P P QQQQQQ P P Ac QQQQQQ QQQQQQ QQQQQQ QQQQQQ QQQQQQ P P QQQQQQ P P Ac Ac Ac QQQQQQ P P Ac Ac QQQQQQ P QQQQQQ P QQQQQQ P P QQQQQQ P P Neuron

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nature medicine volume 16 | number 1 | january 2010 33

in various Huntington’s disease models9. Although we don’t yet know the precise mechanism of protection, there are sev-eral possibilities, including chromatin remodeling, correction of the microtubu-lar transport9 and increased acetylation of huntingtin7. So, histone deacetylase inhibi-tors may have direct and indirect effects on several pathways implicated in Huntington’s disease pathogenesis.

The findings from these three studies show that post-translational modifications of mutant huntingtin are crucial for its clear-ance and highlight the importance of mutant huntingtin abundance in disease pathogen-esis. It will be of interest to test whether phosphorylation and acetylation are gen-eral regulatory mechanisms to target other disease-related, aggregation-prone proteins for degradation.

1. Bates, G. et al. Huntington’s Disease. (Oxford University Press, New York, 2002).

2. Yamamoto, A. et al. Cell 101, 57–66 (2000).3. Arrasate, M. et al. Nature 431, 805–810 (2004).4. Roze, E. et al. Curr. Opin. Neurol. 21, 497–503

(2008).5. Gu, X. et al. Neuron 6, 828–840 (2009).6. Thompson, L.M. et al. J. Cell Biol. 187, 1083–1099

(2009).7. Jeong, H. et al. Cell 137, 60–72 (2009). 8. Ravikumar, B. et al. Nat. Genet. 36, 585–595

(2004).9. Kazantsev, A.G. & Thompson, L.M. Nat. Rev. Drug

Discov. 7, 854–868 (2008).

of the mutant protein.Phosphorylation of huntingtin seems

to promote additional post-translational modifications, including monoubiquitina-tion, polySUMOylation and acetylation of the amino-terminal huntingtin lysines6. Interestingly, another recent study has linked acetylation of mutant huntingtin to its degradation7. Acetylation of huntingtin at Lys9 and Lys444 promotes clearance of the mutant protein by autophagy, whereas a mutant version of huntingtin that cannot be acetylated accumulates and leads to neu-rodegeneration7 (Fig. 1).

Autophagy has been previously impli-cated in Huntington’s disease. For example, administration of small molecules that promote autophagy improves phenotypes in cell and animal models of Huntington’s disease8. However, approaches to target autophagy result in a global and nonspecific modulation that could have deleterious con-sequences for the cell and the organism. By contrast, post-translational modifications might offer an opportunity for more selec-tive clearance of mutant proteins without disrupting other cellular pathways and may therefore be particularly amenable to thera-peutic targeting.

Indeed, histone deacetylase inhibitors have been previously shown as neuroprotective

of mutant huntingtin.Two studies5,6 have now found that clear-

ance of mutant huntingtin can be achieved by post-translational modifications of the mutant protein. The first report, by Gu et al.5, shows that phosphorylation of the amino-terminal fragment of huntingtin at Ser13 and Ser16 residues prevents mutant huntingtin–induced disease pathology in mouse models of Huntington’s disease. Specifically, expression of a mutant version of huntingtin that carried negatively charged aspartic acid residues instead of the two ser-ines to mimic a constitutively phosphor-ylated protein did not result in behavioral deficits, neurodegeneration or accumulation of mutant huntingtin. By contrast, these dis-ease phenotypes were apparent in mice car-rying a mutant huntingtin that had alanine residues instead of serines and could there-fore not be phosphorylated.

The second study, by Thompson et al.6, shows that phsophorylation of Ser13 and Ser16 enhances clearance of huntingtin by the proteasome and by chaperone-mediated autophagy, thereby providing a possible mechanism for the in vivo results of Gu et al.5 (Fig. 1). Thompson et al.6 also found that phosphorylation is more efficient for wild-type than for mutant huntingtin, a difference that may contribute to the pathogenic nature

Vessel remodeling in the newborn: platelets fill the gapRonald Clyman & Sylvain Chemtob

In newborn infants, permanent closure of a major blood vessel connecting the main pulmonary artery to the aorta is essential to allow adequate circulation of blood to major organs. Platelet aggregation now emerges as a crucial step in this process in newborn mice and, possibly, in preterm infants (pages 75–82).

Ronald Clyman is in the Cardiovascular Research

Institute and Department of Pediatrics, University of

California San Francisco, San Francisco, California,

USA. Sylvain Chemtob is in the Departments of

Pediatrics, Ophthalmology and Pharmacology,

Centre Hospitalier Universitaire Ste. Justine,

Montreal, Canada.

e-mail: [email protected]

In the developing fetus, a large blood ves-sel called the ductus arteriosus shunts oxy-genated blood from the placenta away from the unventilated lungs toward major body organs. After birth, when the lungs take over the function of providing oxygen to the body, the ductus arteriosus must be perma-nently sealed off. This closure is initiated by

smooth muscle constriction and narrowing of the lumen, followed by anatomic remodel-ing that turns the vessel into a solid fibrous band.

If the ductus arteriosus fails to close after birth—a condition known as patent ductus arteriosus, which occurs in approximately 60% of preterm newborn infants born after less than 28 weeks of gestation—the result-ing hemodynamic rearrangement can lead to feeding difficulties, pulmonary edema and breathing problems1. Nonsteroidal anti-inflammatory drugs are currently used to close the patent ductus arteriosus in pre-term infants. However, although these drugs effectively induce constriction and narrow-ing of the ductus lumen, they frequently fail

to cause anatomic remodeling and perma-nent closure.

In this issue of Nature Medicine, Echtler et al.2 advance our understanding of the biolog-ical processes required to produce permanent closure of the ductus arteriosus.

In studies in mice, the authors found that the initial constriction of the blood vessel alone is insufficient to completely eliminate blood flow within the lumen of the ductus2. Instead, permanent closure required platelet aggregation and the formation of occlusive thrombi in the ductus lumen (Fig. 1). The authors found that within minutes of birth, when the ductus has already constricted, platelets accumulate in the ductus lumen, leading to thrombus formation2. Mice with

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