Metabolism in HD: Still a relevant mechanism?

Movement Disorders

Volumn 29, Issue 11, 2014, Pages 1366-1374

  Duan, Wenzhen ^a   Jiang, Mali ^a   Jin, Jing ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AMPK; Energy metabolism; Huntington's disease; Mitochondria; PGC 1 ; Sirtuins

Indexed keywords

8 HYDROXYDEOXYGUANOSINE; ADENOSINE DIPHOSPHATE; ADENOSINE PHOSPHATE; ADENOSINE TRIPHOSPHATE; CALCIUM ION; CREATINE; CREATINE KINASE; CYCLOSPORIN A; HUNTINGTIN; LIPOFUSCIN; MITOCHONDRIAL DNA; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PHOSPHOTRANSFERASE; SIRTUIN; SUCCINATE DEHYDROGENASE (UBIQUINONE); UBIDECARENONE; HTT PROTEIN, HUMAN; NERVE PROTEIN; PEPTIDE; POLYGLUTAMINE;

BIOENERGY; BIOGENESIS; BRAIN MITOCHONDRION; CARBONYLATION; DISEASE COURSE; DRUG TARGETING; ENERGY METABOLISM; ENZYME ACTIVITY; ENZYME INHIBITION; GENE MUTATION; HUNTINGTON CHOREA; METABOLIC DISORDER; NERVE DEGENERATION; NERVE FIBER TRANSPORT; NONHUMAN; OXIDATIVE STRESS; PARIETAL CORTEX; PRIORITY JOURNAL; REVIEW; COMPLICATION; GENETICS; HUMAN; METABOLIC DISEASES; METABOLISM;

ADENOSINE TRIPHOSPHATE; ENERGY METABOLISM; HUMANS; HUNTINGTON DISEASE; METABOLIC DISEASES; NERVE TISSUE PROTEINS; PEPTIDES;

EID: 84907959930     PISSN: 08853185     EISSN: 15318257     Source Type: Journal    
DOI: 10.1002/mds.25992     Document Type: Review

References (109)

1. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 1993;72:971-983.
2. Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 1983;306:234-238.
3. Djousse L, Knowlton B, Cupples LA, et al. Weight loss in early stage of Huntington's disease. Neurology 2002;59:1325-1330.
4. Martin JB, Gusella JF. Huntington's disease: pathogenesis and management. N Engl J Med 1986;315:1267-1276.
5. Damiano M, Galvan L, Deglon N, Brouillet E. Mitochondria in Huntington's disease. Biochim Biophys Acta 2010;1802:52-61.
6. Oliveira JM. Mitochondrial bioenergetics and dynamics in Huntington's disease: tripartite synapses and selective striatal degeneration. Journal of Bioenergetics and Biomembranes 2010;42:227-234.
7. Oliveira JM. Nature and cause of mitochondrial dysfunction in Huntington's disease: focusing on huntingtin and the striatum. J Neurochem 2010;114:1-12.
8. Kann O, Kovacs R. Mitochondria and neuronal activity. Am J Physiol Cell Physiol 2007;292:C641-C657.
9. Chen H, Chan DC. Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases. Hum Mol Genet 2009;18:R169-R176.
10. Twig G, Hyde B, Shirihai OS. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 2008;1777:1092-1097.
11. Feigin A, Leenders KL, Moeller JR, et al. Metabolic network abnormalities in early Huntington's disease: an [(18)F]FDG PET study. J Nucl Med 2001;42:1591-1595.
12. Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, Squitieri F. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease. J Nucl Med 2006;47:215-222.
13. Powers WJ, Videen TO, Markham J, McGee-Minnich L, Antenor-Dorsey JV, Hershey T, Perlmutter JS. Selective defect of in vivo glycolysis in early Huntington's disease striatum. Proc Natl Acad Sci U S A 2007;104:2945-2949.
14. Young AB, Penney JB, Starosta-Rubinstein S, et al. PET scan investigations of Huntington's disease: cerebral metabolic correlates of neurological features and functional decline. Ann Neurol 1986;20:296-303.
15. Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR. Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology 1993;43:2689-2695.
16. Garseth M, Sonnewald U, White LR, Rød M, Zwart JA, Nygaard O, Aasly J. Proton magnetic resonance spectroscopy of cerebrospinal fluid in neurodegenerative disease: indication of glial energy impairment in Huntington chorea, but not Parkinson disease. J Neurosci Res 2000;60:779-782.
17. Lim D, Fedrizzi L, Tartari M, Zuccato C, Cattaneo E, Brini M, Carafoli E. Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem 2008;283:5780-5789.
18. Choo YS, Johnson GV, MacDonald M, Detloff PJ, Lesort M. Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet 2004;13:1407-1420.
19. Tabrizi SJ, Cleeter MW, Xuereb J, Taanman JW, Cooper JM, Schapira AH. Biochemical abnormalities and excitotoxicity in Huntington's disease brain. Ann Neurol 1999;45:25-32.
20. Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci 2002;5:731-736.
21. Petrasch-Parwez E, Nguyen HP, Löbbecke-Schumacher M, et al. Cellular and subcellular localization of Huntingtin [corrected] aggregates in the brain of a rat transgenic for Huntington disease. J Comp Neurol 2007;501:716-730.
22. Orr AL, Li S, Wang CE, et al. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci 2008;28:2783-2792.
23. Trushina E, Dyer RB, Badger JD 2nd, et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 2004;24:8195-8209.
24. Li XJ, Orr AL, Li S. Impaired mitochondrial trafficking in Huntington's disease. Biochim Biophys Acta 2010;1802:62-65.
25. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 2006;127:59-69.
26. Ju TC, Chen HM, Lin JT, et al. Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease. J Cell Biol 2011;194:209-227.
27. Choi H, Park CS, Kim BG, Cho JW, Park JB, Bae YS, Bae DS. Creatine kinase B is a target molecule of reactive oxygen species in cervical cancer. Molecules and Cells 2001;12:412-417.
28. Stahl WL, Swanson PD. Biochemical abnormalities in Huntington's chorea brains. Neurology 1974;24:813-819.
29. Gu M, Gash MT, Mann VM, Javoy-Agid F, Cooper JM, Schapira AH. Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 1996;39:385-389.
30. Browne SE, Bowling AC, MacGarvey U, et al. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann Neurol 1997;41:646-653.
31. Benchoua A, Trioulier Y, Zala D, et al. Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol Biol Cell 2006;17:1652-1663.
32. Milakovic T, Quintanilla RA, Johnson GV. Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem 2006;281:34785-34795.
33. Nicholls DG. Mitochondrial calcium function and dysfunction in the central nervous system. Biochim Biophys Acta 2009;1787:1416-1424.
34. Seong IS, Ivanova E, Lee JM, et al. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet 2005;14:2871-2880.
35. Brustovetsky N, Brustovetsky T, Purl KJ, Capano M, Crompton M, Dubinsky JM. Increased susceptibility of striatal mitochondria to calcium-induced permeability transition. J Neurosci 2003;23:4858-4867.
36. Tabrizi SJ, Workman J, Hart PE, et al. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol 2000;47:80-86.
37. Bogdanov MB, Andreassen OA, Dedeoglu A, Ferrante RJ, Beal MF. Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease. J Neurochem 2001;79:1246-1249.
38. Chen CM, Wu YR, Cheng ML, et al. Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington's disease patients. Biochem Biophys Res Commun 2007;359:335-340.
39. Hersch SM, Gevorkian S, Marder K, et al. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Neurology 2006;66:250-252.
40. Sorolla MA, Reverter-Branchat G, Tamarit J, Ferrer I, Ros J, Cabiscol E. Proteomic and oxidative stress analysis in human brain samples of Huntington disease. Free Radic Biol Med 2008;45:667-678.
41. Santamaria A, Pérez-Severiano F, Rodríguez-Martínez E, Maldonado PD, Pedraza-Chaverri J, Ríos C, Segovia J. Comparative analysis of superoxide dismutase activity between acute pharmacological models and a transgenic mouse model of Huntington's disease. Neurochem Res 2001;26:419-424.
42. Goswami A, Dikshit P, Mishra A, Mulherkar S, Nukina N, Jana NR. Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction. Biochem Biophys Res Commun 2006;342:184-190.
43. Gines S, Seong IS, Fossale E, et al. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum Mol Genet 2003;12:497-508.
44. Mochel F, Durant B, Meng X, et al. Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 2012;287:1361-1370.
45. Sorolla MA, Rodríguez-Colman MJ, Tamarit J, et al. Protein oxidation in Huntington disease affects energy production and vitamin B6 metabolism. Free Radic Biol Med 2010;49:612-621.
46. Siddiqui A, Rivera-Sánchez S, Castro Mdel R, et al. Mitochondrial DNA damage is associated with reduced mitochondrial bioenergetics in Huntington's disease. Free Radic Biol Med 2012;53:1478-1488.
47. Kim J, Moody JP, Edgerly CK, et al. Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease. Hum Mol Genet 2010;19:3919-3935.
48. Song W, Chen J, Petrilli A, et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 2011;17:377-382.
49. Shirendeb UP, Calkins MJ, Manczak M, et al. Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease. Hum Mol Genet 2012;21:406-420.
50. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metabol 2005;1:361-370.
51. Scarpulla RC. Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem 2006;97:673-683.
52. Lin J, Wu PH, Tarr PT, et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 2004;119:121-135.
53. Chaturvedi RK, Adhihetty P, Shukla S, et al. Impaired PGC-1alpha function in muscle in Huntington's disease. Hum Mol Genet 2009;18:3048-3065.
54. Chaturvedi RK, Calingasan NY, Yang L, Hennessey T, Johri A, Beal MF. Impairment of PGC-1alpha expression, neuropathology and hepatic steatosis in a transgenic mouse model of Huntington's disease following chronic energy deprivation. Hum Mol Genet 2010;19:3190-3205.
55. Weydt P, Pineda VV, Torrence AE, et al. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab 2006;4:349-362.
56. Chiang MC, Chen CM, Lee MR, et al. Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma. Hum Mol Genet 2010;19:4043-4058.
57. Soyal SM, Felder TK, Auer S, et al. A greatly extended PPARGC1A genomic locus encodes several new brain-specific isoforms and influences Huntington disease age of onset. Hum Mol Genet 2012;21:3461-3473.
58. Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 2006;116:1776-1783.
59. Ramamurthy S, Ronnett GV. Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain. J Physiol 2006;574:85-93.
60. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis: nature reviews. Mol Cell Biol 2012;13:251-262.
61. Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev 2009;89:1025-1078.
62. Kemp BE, et al. Dealing with energy demand: the AMP-activated protein kinase. Trends Biochem Sci 1999;24:22-25.
63. Ma TC, Buescher JL, Oatis B, et al. Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci Lett 2007;411:98-103.
64. Chou SY, Lee YC, Chen HM, et al. CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. J Neurochem 2005;93:310-320.
65. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000;80:1107-1213.
66. Zhang SF, Hennessey T, Yang L, Starkova NN, Beal MF, Starkov AA. Impaired brain creatine kinase activity in Huntington's disease. Neurodegen Dis 2011;8:194-201.
67. Luthi-Carter R, Hanson SA, Strand AD, et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet 2002;11:1911-1926.
68. Li H, Khirug S, Cai C, et al. KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 2007;56:1019-1033.
69. Spires TL, Grote HE, Garry S, et al. Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice. Eur J Neurosci 2004;19:2799-2807.
70. Aksenov M, Aksenova M, Butterfield DA, Markesbery WR. Oxidative modification of creatine kinase BB in Alzheimer's disease brain. J Neurochem 2000;74:2520-2527.
71. Mekhfi H, Veksler V, Mateo P, Maupoil V, Rochette L, Ventura-Clapier R. Creatine kinase is the main target of reactive oxygen species in cardiac myofibrils. Circ Res 1996;78:1016-1027.
72. Firdaus WJ, Wyttenbach A, Giuliano P, Kretz-Remy C, Currie RW, Arrigo AP. Huntingtin inclusion bodies are iron-dependent centers of oxidative events. FEBS J 2006;273:5428-5441.
73. Morris M. Dementia and cognitive changes in Huntington's disease. Adv Neurol 1995;65:187-200.
74. Petersen A, Castilho RF, Hansson O, Wieloch T, Brundin P. Oxidative stress, mitochondrial permeability transition and activation of caspases in calcium ionophore A23187-induced death of cultured striatal neurons. Brain Res 2000;857:20-29.
75. Leventhal L, Sortwell CE, Hanbury R, Collier TJ, Kordower JH, Palfi S. Cyclosporin A protects striatal neurons in vitro and in vivo from 3-nitropropionic acid toxicity. J Comp Neurol 2000;425:471-478.
76. Merlini L, Angelin A, Tiepolo T, et al. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies. Proc Natl Acad Sci U S A 2008;105:5225-5229.
77. Fernandes HB, Baimbridge KG, Church J, Hayden MR, Raymond LA. Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington's disease. J Neurosci 2007;27:13614-13623.
78. Duan W. Sirtuins: from metabolic regulation to brain aging. Front Aging Neurosci 2013;5:36.
79. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:113-118.
80. Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med 2012;18:153-158.
81. Jeong H, Cohen DE, Cui L, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 2012;18:159-165.
82. Yang T, Chan NY, Sauve AA. Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem 2007;50:6458-6461.
83. Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1alpha and BDNF gene expression in a mouse model of Huntington's disease. Neurobiol Dis 2011;41:43-50.
84. Fu J, Jin J, Cichewicz RH, et al. Trans-(-)-epsilon-viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington disease. J Biol Chem 2012;287:24460-24472.
85. Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Néri C. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 2005;37:349-350.
86. Ho DJ, Calingasan NY, Wille E, Dumont M, Beal MF. Resveratrol protects against peripheral deficits in a mouse model of Huntington's disease. Exp Neurol 2010;225:74-84.
87. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006;127:1109-1122.
88. Sinclair DA, Guarente L. Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol 2014;54:363-380.
89. Hubbard BP, Gomes AP, Dai H, et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 2013;339:1216-1219.
90. Smith MR, Syed A, Lukacsovich T, et al. A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease. Hum Mol Genet 2014;1:2995-3007.
91. Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci 2010;123:4251-4258.
92. Chopra V, Quinti L, Kim J, et al. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models. Cell Rep 2012;2:1492-1497.
93. Johri A, Calingasan NY, Hennessey TM, et al. Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease. Hum Mol Genet 2012;21:1124-1137.
94. Strum JC, Shehee R, Virley D, et al. Rosiglitazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis 2007;11:45-51.
95. Quintanilla RA, Jin YN, Fuenzalida K, Bronfman M, Johnson GV. Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells: possible role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in the pathogenesis of Huntington disease. J Biol Chem 2008;283:25628-25637.
96. Jin J, Albertz J, Guo Z, et al. Neuroprotective effects of PPAR-gamma agonist rosiglitazone in N171-82Q mouse model of Huntington's disease. J Neurochem 2013;125:410-419.
97. Beal MF, Shults CW. Effects of coenzyme Q10 in Huntington's disease and early Parkinson's disease. BioFactors 2003;18:153-161.
98. Hickey MA, Zhu C, Medvedeva V, Franich NR, Levine MS, Chesselet MF. Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease. Mol Cell Neurosci 2012;49:149-157.
99. Spindler M, Beal MF, Henchcliffe C. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatric Dis Treat 2009;5:597-610.
100. Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, Beal MF. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases. J Neurochem 2009;109:1427-1439.
101. Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model. Neurosci Lett 2001;5:149-153.
102. Menalled LB, Patry M, Ragland N, et al. Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline. PloS One 2010;5:e9793.
103. Huntington Study G. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 2001;57:397-404.
104. Huntington Study Group Pre CI, Hyson HC, Kieburtz K, et al. Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects. Mov Disord 2010;25:1924-1928.
105. Lin YS, Chen CM, Soong BW, et al. Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease. J Clin Invest 2011;121:1519-1523.
106. Ferrante RJ, Andreassen OA, Jenkins BG, et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J Neurosci 2000;20:4389-4397.
107. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR. Functions and effects of creatine in the central nervous system. Brain Res Bull 2008;76:329-343.
108. Perasso L, Cupello A, Lunardi GL, Principato C, Gandolfo C, Balestrino M. Kinetics of creatine in blood and brain after intraperitoneal injection in the rat. Brain Res 2003;974:37-42.
109. Rosas HD, Doros G, Gevorkian S, et al. PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology 2014;82:850-857.