Mitochondria and Huntington's disease pathogenesis: Insight from genetic and chemical models

Annals of the New York Academy of Sciences

Volumn 1147, Issue , 2008, Pages 358-382

  Browne, Susan E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

3 nitropropionic acid; Apoptosis; Calcium; Huntingtin; Huntington; Metabolism; Mitochondria; Mouse; Neurodegeneration; Nucleus; Toxin

Indexed keywords

3 NITROPROPIONIC ACID; HUNTINGTIN; NEUROTOXIN;

APOPTOSIS; BRAIN METABOLISM; BRAIN TISSUE; CADAVER; CALCIUM TRANSPORT; CELL ENERGY; CHEMICAL MODEL; CONFERENCE PAPER; DEGENERATIVE DISEASE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; EXCITOTOXICITY; GENE DELETION; GENE DISRUPTION; GENETIC ANALYSIS; HUMAN; HUNTINGTON CHOREA; IN VIVO STUDY; MITOCHONDRIAL GENETICS; MITOCHONDRIAL RESPIRATION; MUSCLE TISSUE; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN PROTEIN INTERACTION; RESPIRATORY CHAIN;

ANIMALIA;

EID: 57649187103     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1196/annals.1427.018     Document Type: Conference Paper

References (142)

1. Vonsattel, J.P.G. & M. DiFiglia. 1998. Huntington Disease. J. Neuropathol. Exp. Neurol. 57 : 369 384.
2. Duff, K., J.S. Paulsen, L.J. Beglinger, et al. 2007. Psychiatric symptoms in Huntington's disease before diagnosis: the predict-HD study. Biol. Psychiatry 62 : 1341 1346.
3. The Huntington's Disease Collaborative Research Group. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72 : 971 983.
4. Harjes, P. & E.E. Wanker. 2003. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem. Sci. 28 : 425 433.
5. Pal, A., F. Severin, B. Lommer, et al. 2006. Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease. J. Cell Biol. 172 : 605 618.
6. Gunawardena, S., L.S. Her, R.G. Brusch, et al. 2003. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40 : 25 40.
7. Rong, J., J.R. McGuire, Z.H. Fang, et al. 2006. Regulation of intracellular trafficking of huntingtin-associated protein-1 is critical for TrkA protein levels and neurite outgrowth. J. Neurosci. 26 : 6019 6030.
8. Trushina, E., R.B. Dyer, J.D. Badger, 2nd., et al. 2004. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol. Cell Biol. 24 : 8195 8209.
9. Ross, C.A. & L.M. Thompson. 2006. Transcription meets metabolism in neurodegeneration. Nat. Med. 12 : 1239 1241.
10. Zucker, B., R. Luthi-Carter, J.A. Kama, et al. 2005. Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1. Hum. Mol. Genet. 14 : 179 189.
11. Milnerwood, A.J. & L.A. Raymond. 2007. Corticostriatal synaptic function in mouse models of Huntington's disease: Early effects of huntingtin repeat length and protein load. J. Physiol. 585 : 817 831.
12. Smith, R., P. Brundin & J.Y. Li. 2005. Synaptic dysfunction in Huntington's disease: a new perspective. Cell Mol. Life Sci. 62 : 1901 1912.
13. Rangone, H., S. Humbert & F. Saudou. 2004. Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic? Pathol. Biol. (Paris) 52 : 338 342.
14. Yu, Z.X., S.H. Li, J. Evans, et al. 2003. Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington's disease. J. Neurosci. 23 : 2193 2202.
15. Browne, S.E. & M.F. Beal. 2004. The energetics of Huntington's disease. Neurochem. Res. 29 : 531 546.
16. Rego, A.C. & L.P. de Almeida. 2005. Molecular targets and therapeutic strategies in Huntington's disease. Curr. Drug Targets CNS Neurol. Disord. 4 : 361 381.
17. Sawa, A. 2001. Mechanisms for neuronal cell death and dysfunction in Huntington's disease: pathological cross-talk between the nucleus and the mitochondria? J. Mol. Med. 79 : 375 381.
18. Djousse, L., B. Knowlton, L.A. Cupples, et al. 2002. Weight loss in early stage of Huntington's disease. Neurology 59 : 1325 1330.
19. Mahant, N., E.A. McCusker, K. Byth, et al. 2003. Huntington's disease: clinical correlates of disability and progression. Neurology 61 : 1085 1092.
20. Sánchez-Pernaute, R., J.M. García-Segura, A. del Barrio Alba, et al. 1999. Clinical correlation of striatal 1H MRS changes in Huntington's disease. Neurology 53 : 806 812.
21. Reynolds, N.C. Jr., R.W. Prost & L.P. Mark. 2005. Heterogeneity in 1H-MRS profiles of presymptomatic and early manifest Huntington's disease. Brain Res. 1031 : 82 89.
22. Ruocco, H.H., I. Lopes-Cendes, L.M. Li & F. Cendes. 2007. Evidence of thalamic dysfunction in Huntington disease by proton magnetic resonance spectroscopy. Mov. Disord. 22 : 2052 2056.
23. Clark, J.B. 1998. N-Acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev. Neurosci. 20 : 271 276.
24. Moffett, J.R., B. Ross, P. Arun, et al. 2007. N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog. Neurobiol. 81 : 89 131.
25. Jenkins, B.G., W.J. Koroshetz, M.F. Beal & B.R. Rosen. 1993. Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology 43 : 2689 2695.
26. Koroshetz, W.J., B.G. Jenkins, B.R. Rosen & M.F. Beal. 1997. Energy metabolism defects in Huntington's disease and effects of coenzyme Q10. Ann. Neurol. 41 : 160 165.
27. Schapiro, M., K.M. Cecil, J. Doescher, et al. 2004. MR imaging and spectroscopy in juvenile Huntington disease. Pediatr. Radiol. 34 : 640 643.
28. van Oostrom, J.C., P.E. Sijens, R.A. Roos & K.L. Leenders. 2007. 1H magnetic resonance spectroscopy in preclinical Huntington disease. Brain Res. 1168 : 67 71.
29. Kuwert, T., H.W. Lange, K.J. Langen, et al. 1990. Cortical and subcortical glucose consumption measured by PET in patients with Huntington's disease. Brain 113 : 1405 1423.
30. Antonini, A., K.L. Leenders, R. Spiegel, et al. 1996. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's disease. Brain 119 : 2085 2095.
31. Kuwert, T., H.W. Lange, H. Boecker, et al. 1993. Striatal glucose consumption in chorea-free subjects at risk of Huntington's disease. J. Neurol. 241 : 31 36.
32. Ciarmiello, A., M. Cannella, S. Lastoria, et al. 2006. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease. J. Nucl. Med. 47 : 215 222.
33. Feigin, A., K.L. Leenders, J.R. Moeller, et al. 2001. Metabolic network abnormalities in early Huntington's Disease: an [(18) F] FDG PET study. J. Nucl. Med. 42 : 1591 1595.
34. Feigin, A., C. Tang, Y. Ma, et al. 2007. Thalamic metabolism and symptom onset in preclinical Huntington's disease. Brain 130 : 2858 2867.
35. Bäckman, L. & L. Farde. 2001. Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging. Scand. J. Psychol. 42 : 287 296.
36. Squitieri, F., A. Ciarmiello, S. Di Donato & L. Frati. 2006. The search for cerebral biomarkers of Huntington's disease: a review of genetic models of age at onset prediction. Eur. J. Neurol. 13 : 408 415.
37. Kipps, C.M., A.J. Duggins, N. Mahant, et al. 2005. Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study. J. Neurol. Neurosurg. Psychiatry 76 : 650 655.
38. Browne, S.E., J.-P.P. DiMauro, R.J. Albrecht & H.N. Burr. 2003. The evolution of metabolic defects in a knock-in mutant mouse model of huntington's disease. Soc. Neurosci. Abstr. 130.12.
39. Goebel, H.H., R. Heipertz, W. Scholz, et al. 1978. Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies. Neurology 28 : 23 31.
40. Squitieri, F., M. Cannella, G. Sgarbi, et al. 2006. Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Mech. Ageing Dev. 127 : 217 220.
41. Choo, Y.S., G.V. Johnson, M. MacDonald, et al. 2004. Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum. Mol. Genet. 13 : 1407 1420.
42. Brennan, W.A., E.D. Bird & J.R. Aprille. 1985. Regional mitochondrial respiratory activity in Huntington's disease brain. J. Neurochem. 44 : 1948 1950.
43. Browne, S.E., A.C. Bowling, U. MacGarvey, et al. 1997. Oxidative damage and metabolic dysfunction in Huntington's Disease: Selective vulnerability of the basal ganglia. Ann. Neurol. 41 : 646 653.
44. Gu, M., M.T. Gash, V.M. Mann, et al. 1996. Mitochondrial defect in Huntington's disease caudate nucleus. Ann. Neurol. 39 : 385 389.
45. Mann, V.M., J.M. Cooper, F. Javoy-Agid, et al. 1990. Mitochondrial function and parental sex effect in Huntington's disease. Lancet 36 : 749.
46. Tabrizi, S.J., M.W. Cleeter, J. Xuereb, et al. 1999. Biochemical abnormalities and excitotoxicity in Huntington's disease brain. Ann. Neurol. 45 : 25 32.
47. Butterworth, J., C.M. Yates & G.P. Reynolds. 1985. Distribution of phosphate-activated glutaminase, succinic dehydrogenase, pyruvate dehydrogenase, and α-glutamyl transpeptidase in postmortem brain from Huntington's disease and agonal cases. J. Neurol. Sci. 67 : 161 171.
48. Klivenyi, P., A.A. Starkov, N.Y. Calingasan, et al. 2004. Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J. Neurochem. 88 : 1352 1360.
49. Benchoua, A., Y. Trioulier, D. Zala, et al. 2006. Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol. Biol. Cell. 17 : 1652 1663.
50. Guidetti, P., V. Charles, E.Y. Chen, et al. 2001. Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp. Neurol. 169 : 340 350.
51. Powers, W.J., T.O. Videen, J. Markham, et al. 2007. Selective defect of in vivo glycolysis in early Huntington's disease striatum. Proc. Natl. Acad. Sci. USA 104 : 2945 2949.
52. Lodi, R., A.H. Schapira, D. Manners, et al. 2000. Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy. Ann. Neurol. 48 : 72 76.
53. Saft, C., J. Zange, J. Andrich, et al. 2005. Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease. Mov. Disord. 20 : 674 679.
54. Schapira, A. & R. Lodi. 2004. Assessment of in vitro and in vivo mitochondrial function in Friedreich's ataxia and Huntington's disease. Methods Mol. Biol. 277 : 293 307.
55. Ciammola, A., J. Sassone, L. Alberti, et al. 2006. Increased apoptosis, Huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects. Cell Death Differ. 13 : 2068 2078.
56. Panov, A.V., C.A. Gutekunst, B.R. Leavitt, et al. 2002. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat. Neurosci. 5 : 731 736.
57. 2+-induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington's disease individuals. Mol. Cell Biochem. 269 : 143 152.
58. Sawa, A., G.W. Wiegand, J. Cooper, et al. 1999. Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nature Med. 5 : 1194 1198.
59. Seong, I.S., E. Ivanova, J.M. Lee, et al. 2005. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum. Mol. Genet. 14 : 2871 2880.
60. Paulsen, J.S., D.R. Langbehn, J.C. Stout, et al. 2008. Detection of Huntington's disease decades before diagnosis: The Predict HD study. J. Neurol. Neurosurg. Psychiatry 79 : 874 880.
61. Levine, M.S., C. Cepeda, M.A. Hickey, et al. 2004. Genetic mouse models of Huntington's and Parkinson's diseases: illuminating but imperfect. Trends Neurosci. 27 : 691 697.
62. Menalled, L.B. 2005. Knock-in mouse models of Huntington's disease. NeuroRx. 2 : 465 470.
63. Slow, E.J., J. van Raamsdonk, D. Rogers, et al. 2003. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 12 : 1555 1567.
64. Van Raamsdonk, J.M., J. Pearson, E.J. Slow, et al. 2005. Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease. J. Neurosci. 25 : 4169 4180.
65. Q111 knock-in mice. Hum. Mol. Genet. 9 : 503 513.
66. Menalled, L.B., J.D. Sison, I. Dragatsis, et al. 2003. Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats. J. Comp. Neurol. 465 : 11 26.
67. Hurlbert, M.S., W. Zhou, C. Wasmeier, et al. 1999. Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes 48 : 649 651.
68. Andreassen, O.A., A. Dedeoglu, R.J. Ferrante, et al. 2001. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease. Neurobiol. Dis. 8 : 479 491.
69. Mangiarini, L., K. Sathasivam, M. Seller, et al. 1996. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87 : 493 506.
70. Schilling, G., M.W. Becher, A.H. Sharp, et al. 1999. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 8 : 397 407.
71. Stack, E.C., J.K. Kubilus, K. Smith, et al. 2005. Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice. J. Comp. Neurol. 490 : 354 370.
72. Ferrante, R.J., O.A. Andreassen, A. Dedeoglu, et al. 2002. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J. Neurosci. 22 : 1592 1599.
73. Mihm, M.J., D.M. Amann, B.L. Schanbacher, et al. 2007. Cardiac dysfunction in the R6/2 mouse model of Huntington's disease. Neurobiol. Dis. 25 : 297 308.
74. Hodgson, J.G., N. Agopyan, C.A. Gutekunst, et al. 1999. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23 : 181 192.
75. Shirasaki, D.I., M. Gray, T.K. Murphy, et al. 2007. A proteomic probing of the full-length huntingtin interactome based on a novel BAC transgenic mouse model of Huntington's disease. Soc. Neurosci. Abstracts 764.5.
76. White, J.K., W. Auerbach, M.P. Duyao, et al. 1997. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat. Genet. 17 : 404 410.
77. Heng, M.Y., S.J. Tallaksen-Greene, P.J. Detloff & R.L. Albin. 2007. Longitudinal evaluation of the Hdh(CAG)150 knock-in murine model of Huntington's disease. J. Neurosci. 27 : 8989 8998.
78. Levine, M.S., G.J. Klapstein, A. Koppel, et al. 1999. Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. J. Neurosci. Res. 58 : 515 532.
79. Wheeler, V.C., C.A. Gutekunst, V. Vrbanac, et al. 2002. Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum. Mol. Genet. 11 : 633 640.
80. Brustovetsky, N., R. LaFrance, K.J. Purl, et al. 2005. Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's disease. J. Neurochem. 93 : 1361 1370.
81. Trettel, F., D. Rigamonti, P. Hilditch-Maguire, et al. 2000. Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum. Mol. Genet. 9 : 2799 809.
82. Gutekunst, C.A., S.H. Li, H. Yi, et al. 1998. The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human. J. Neurosci. 18 : 7674 7686.
83. Petrasch-Parwez, E., H.P. Nguyen, M. Löbbecke-Schumacher, et al. 2007. Cellular and subcellular localization of Huntingtin [corrected] aggregates in the brain of a rat transgenic for Huntington disease. J. Comp. Neurol. 501 : 716 730.
84. Jenkins, B.G., P. Klivenyi, E. Kustermann, et al. 2000. Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington's disease mice. J. Neurochem. 74 : 2108 119.
85. Jenkins, B.G., O.A. Andreassen, A. Dedeoglu, et al. 2005. Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington's disease. J. Neurochem. 95 : 553 562.
86. Tkac, I., J.M. Dubinsky, C.D. Keene, et al. 2007. Neurochemical changes in Huntington R6/2 mouse striatum detected by in vivo 1H NMR spectroscopy. J. Neurochem. 100 : 1397 1406.
87. van Dellen, A., J. Welch, R.M. Dixon, et al. 2000. N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice. Neuroreport 11 : 3751 3757.
88. Tsang, T.M., B. Woodman, G.A. McLoughlin, et al. 2006. Metabolic characterization of the R6/2 transgenic mouse model of Huntington's disease by high-resolution MAS 1H NMR spectroscopy. J. Proteome Res. 5 : 483 492.
89. Tabrizi, S.J., J. Workman, P.E. Hart, et al. 2000. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann. Neurol. 47 : 80 86.
90. Perluigi, M., H.F. Poon, W. Maragos, et al. 2005. Proteomic analysis of protein expression and oxidative modification in r6/2 transgenic mice: a model of Huntington disease. Mol. Cell Proteomics 4 : 1849 1861.
91. Gizatullina, Z.Z., K.S. Lindenberg, P. Harjes, et al. 2006. Low stability of Huntington muscle mitochondria against Ca2+ in R6/2 mice. Ann. Neurol. 59 : 407 411.
92. Lee, J.M., E.V. Ivanova, I.S. Seong, et al. 2007. Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet. 3 : e135.
93. Milakovic, T. & G.V. Johnson. 2005. Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J. Biol. Chem. 280 : 30773 30782.
94. Brouillet, E., C. Jacquard, N. Bizat & D. Blum. 2005. 3-Nitropropionic acid: a mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington's disease. J. Neurochem. 95 : 1521 1540.
95. Gines, S., I.S. Seong, E. Fossale, et al. 2003. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum. Mol. Genet. 12 : 497 508.
96. Ruan, Q., M. Lesort, M.E. MacDonald & G.V. Johnson. 2004. Striatal cells from mutant huntingtin knock-in mice are selectively vulnerable to mitochondrial complex II inhibitor-induced cell death through a non-apoptotic pathway. Hum. Mol. Genet. 13 : 669 681.
97. Puranam, K.L., G. Wu, W.J. Strittmatter & J.R. Burke. 2006. Polyglutamine expansion inhibits respiration by increasing reactive oxygen species in isolated mitochondria. Biochem. Biophys. Res. Commun. 341 : 607 613.
98. Panov, A.V., J.R. Burke, W.J. Strittmatter & J.T. Greenamyre. 2003. In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease. Arch. Biochem. Biophys. 410 : 1 6.
99. Milakovic, T., R.A. Quintanilla & G.V. Johnson. 2006. Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J. Biol. Chem. 281 : 34785 34795.
100. Oliveira, J.M., M.B. Jekabsons, S. Chen, et al. 2007. Mitochondrial dysfunction in Huntington's disease: the bioenergetics of isolated and in situ mitochondria from transgenic mice. J. Neurochem. 101 : 241 249.
101. Chalmers, S. & D.G. Nicholls. 2004. The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. J. Biol. Chem. 278 : 19062 19070.
102. Jekabsons, M.B. & D.G. Nicholls. 2004. In situ respiration and bioenergetic status of mitochondria in primary cerebellar granule neuronal cultures exposed continuously to glutamate. J. Biol. Chem. 279 : 32989 33000.
103. Fernandes, H.B., K.G. Baimbridge, J. Church, et al. 2007. Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington's disease. J. Neurosci. 27 : 13614 13623.
104. Beal, M.F. 1994. Huntington's disease, energy, and excitotoxicity. Neurobiol. Aging 15 : 275 276.
105. Cepeda, C., M.A. Ariano, C.R. Calvert, et al. 2001. NMDA receptor function in mouse models of Huntington disease. J. Neurosci. Res. 66 : 525 539.
106. Shehadeh, J., H.B. Fernandes, M.M. Zeron Mullins, et al. 2006. Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Neurobiol. Dis. 21 : 392 403.
107. Zeron, M.M., H.B. Fernandes, C. Krebs, et al. 2004. Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease. Mol. Cell Neurosci. 25 : 469 479.
108. Tang, T.S., X. Chen, J. Liu & I. Bezprozvanny. 2007. Dopaminergic signaling and striatal neurodegeneration in Huntington's disease. J. Neurosci. 27 : 7899 7910.
109. Tang, T.S., E. Slow, V. Lupu, et al. 2005. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc. Natl. Acad. Sci. USA 102 : 2602 2607.
110. Jarabek, B.R., R.P. Yasuda & B.B. Wolfe. 2004. Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model. Brain 127 : 505 516.
111. Hansson, O., E. Guatteo, N.B. Mercuri, et al. 2001. Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene. Eur. J. Neurosci. 14 : 1492 1504.
112. Petersén, A., O. Hansson, Z. Puschban, et al. 2001. Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine. Eur J. Neurosci. 14 : 1425 1135.
113. Morton, A.J. & W. Leavens. 2000. Mice transgenic for the human Huntington's disease mutation have reduced sensitivity to kainic acid toxicity. Brain Res. Bull. 52 : 51 59.
114. Snider, B.J., J.L. Moss, F.J. Revilla, et al. 2003. Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults. Neuroscience 120 : 617 625.
115. Song, C., Y. Zhang, C.G. Parsons & Y.F. Liu. 2003. Expression of polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N-methyl-D-aspartate receptors. J. Biol. Chem. 278 : 33364 33369.
116. Jakel, R.J. & W.F. Maragos. 2000. Neuronal cell death in Huntington's disease: a potential role for dopamine. Trends Neurosci. 23 : 239 245.
117. Poeggeler, B., A. Rassoulpour, H.Q. Wu, et al. 2007. Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-D-aspartate neurotoxicity. Neuroscience 148 : 188 197.
118. Browne, S.E. & M.F. Beal. 2006. Oxidative damage in Huntington's disease pathogenesis. Antioxid Redox Signal. 8 : 2061 2073.
119. Trushina, E. & C.T. McMurray. 2007 Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 145 : 1233 1248.
120. Stack, E., W.R. Matson & R.J. Ferrante. 2008. Evidence of oxidant damage in Huntington's disease: Translational strategies using antioxidants. Proc NY Acad Sci. In press.
121. Gardian, G., S.E. Browne, D.K. Choi, et al. 2005. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease. J. Biol. Chem. 280 : 556 563.
122. Reiner, A., I. Dragatsis, S. Zeitlin & D. Goldowitz. 2003. Wild-type huntingtin plays a role in brain development and neuronal survival. Mol. Neurobiol. 28 : 259 276.
123. Gines, S., E. Ivanova, I.S. Seong, et al. 2003. Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-D-aspartate receptor activation in Huntington's disease knock-in striatal cells. J. Biol. Chem. 278 : 50514 50522.
124. Majumder, P., B. Chattopadhyay, A. Mazumder, et al. 2006. Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1. Neurobiol. Dis. 22 : 242 256.
125. Graham, R.K., Y. Deng, E.J. Slow, et al. 2006. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125 : 1179 1191.
126. Browne, S.E. & M.F. Beal. 2002. Toxin-induced mitochondrial dysfunction. Int. Rev. Neurobiol. 53 : 243 279.
127. Ramaswamy, S., J.L. McBride & J.H. Kordower. 2007. Animal models of Huntington's disease. ILAR J. 48 : 356 373.
128. Fernandez-Gomez, F.J., M. Gomez-Lazaro, D. Pastor, et al. 2005. Minocycline fails to protect cerebellar granular cell cultures against malonate-induced cell death. Neurobiol. Dis. 20 : 384 391.
129. Nasr, P., H.I. Gursahani, Z. Pang, et al. 2003. Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid. Neurochem. Int. 43 : 89 99.
130. Cui, L., H. Jeong, F. Borovecki, et al. 2006. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127 : 59 69.
131. La Piana, G., D. Marzulli, V. Gorgoglione & N.E. Lofrumento. 2005. Porin and cytochrome oxidase containing contact sites involved in the oxidation of cytosolic NADH. Arch. Biochem. Biophys. 436 : 91 100.
132. Xia, J., D.H. Lee, J. Taylor, et al. 2003. Huntingtin contains a highly conserved nuclear export signal. Hum. Mol. Genet. 12 : 1393 1403.
133. Kuhn, A., D.R. Goldstein, A. Hodges, et al. 2007. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum. Mol. Genet. 16 : 1845 1861.
134. Bae, B.I., H. Xu, S. Igarashi, et al. 2005. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron 47 : 29 41.
135. Chen-Plotkin, A.S., G. Sadri-Vakili, G.J. Yohrling, et al. 2006. Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease. Neurobiol. Dis. 22 : 233 241.
136. Steffan, J.S., A. Kazantsev, O. Spasic-Boskovic, et al. 2000. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA 97 : 6763 6768.
137. Lee, J., C.H. Kim, D.K. Simon, et al. 2005. Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival. J. Biol. Chem. 280 : 40398 40401.
138. Weydt, P., V.V. Pineda, A.E. Torrence, et al. 2006. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab. 4 : 349 362.
139. Feng, Z., S. Jin, A. Zupnick, et al. 2006. p53 tumor suppressor protein regulates the levels of huntingtin gene expression. Oncogene 25 : 1 7.
140. Ryan, A.B., S.O. Zeitlin & H. Scrable. 2006. Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis. Neurobiol. Dis. 24 : 419 427.
141. Suzuki, M. & T. Koike. 2005. Early apoptotic and late necrotic components associated with altered Ca2+ homeostasis in a peptide-delivery model of polyglutamine-induced neuronal death. J. Neurosci. Res. 80 : 549 561.
142. Tang, T.S., H. Tu, P.C. Orban, et al. 2004. HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca release in primary culture of striatal medium spiny neurons. Eur J. Neurosci. 20 : 1779 1787.