小腦脊髓運動失調症第三型(spinocerebellar ataxia type 3; SCA3)，亦稱Machado–Joseph disease (MJD)，為小腦脊髓運動失調症眾多亞型中最常見的一型，屬於晚發性自體顯性遺傳的神經退化性疾病。主要是因為座落於14q24.3-q32的MJD1基因發生CAG三核苷酸過度擴增的現象，這些擴增的CAG序列會轉譯出含多麩醯胺酸(polyglutamine; polyQ)序列的蛋白質產物ataxin3 (AT3)，突變的AT3會在細胞內聚集，透過蛋白質水解機制切割後，在細胞核內形成包含體(nuclear inclusions; NIs)產生細胞毒性使得細胞死亡。目前SCA3實際的致病機轉尚未明瞭，為了解AT3與SCA3病程中的致病機制，我們建立AT3誘導表現的PC12細胞模式。我們發現75Q細胞在氧化壓力以及蛋白質酶抑制劑處理過後會比27Q細胞更容易產生蛋白質聚集在細胞核以及細胞和周圍的現象，對於壓力藥物的耐受性也比27Q細胞要低許多。因此我們藉由建立的SCA3細胞模式做一系列新穎組蛋白去乙醯酶抑制劑(histone deacetylase inhibitors; HDACi)藥物篩選，結果發現某些抑制劑藥物確實能保護SCA3細胞，提升細胞存活率以及神經細胞分支生長，降低氧化壓力以及蛋白質聚集的現象，並增加組蛋白(histone)乙醯化及活化許多具神經保護性的訊息傳遞路徑例如Hsp27、ERK、 MnSOD 和NF-κB等。因此，組蛋白去乙醯酶抑制劑藥物或許可成為治療SCA3的良好候選療法。

Spinocerebellar ataxia type 3 (SCA3), also called Machado–Joseph disease (MJD), is an autosomal dominant neurodegenerative disease results from expanded CAG repeat of MJD1 gene. The CAG repeat expansion encodes polyglutamine (polyQ) stretch in mutant ataxin-3 protein and causes protein cleaved, insoluble, accumulated and aggregated in the neurons. These inclusions further elevate cellular oxidative stress and lead to cell death. We established inducible cell system expressing human full length ataxin-3 containing 27Q or 75Q in PC12 cells. Cells with 75Q ataxin-3 showed lower viability and more nuclear/peri-nuclear aggregation in stress environments. We tested several novel HDAC inhibitor (HDACi) compounds in the inducible SCA3 cells. Our results show that some HDACi could elevate cell viability, reduce aggregation and promote neurite outgrowth. We also observed that HDACi could increase histone acetylation and activate neuroprotective proteins, such as Hsp27, ERK pathway regulators, MnSOD and NF-κB. These findings indicate that some novel HDACi compounds might be potential for SCA3 treatment.

Aletta JM (1996) Phosphorylation of type III beta-tubulin PC12 cell neurites during NGF-induced process outgrowth. J Neurobiol 31:461-475.
Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, Schweitzer ES, Olson JM, Kazantsev A, Marsh JL, Thompson LM (2006) Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum Mol Genet 15:273-285.
Barbeau A, Roy M, Cunha L, de Vincente AN, Rosenberg RN, Nyhan WL, MacLeod PL, Chazot G, Langston LB, Dawson DM, et al. (1984) The natural history of Machado-Joseph disease. An analysis of 138 personally examined cases. Can J Neurol Sci 11:510-525.
Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552-1555.
Benn CL, Butler R, Mariner L, Nixon J, Moffitt H, Mielcarek M, Woodman B, Bates GP (2009) Genetic knock-down of HDAC7 does not ameliorate disease pathogenesis in the R6/2 mouse model of Huntington's disease. PLoS One 4:e5747.
Berke SJ, Schmied FA, Brunt ER, Ellerby LM, Paulson HL (2004) Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem 89:908-918.
Berke SJ, Chai Y, Marrs GL, Wen H, Paulson HL (2005) Defining the role of ubiquitin-interacting motifs in the polyglutamine disease protein, ataxin-3. J Biol Chem 280:32026-32034.
Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW, Lee CM (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci U S A 97:11074-11079.
Bichelmeier U, Schmidt T, Hubener J, Boy J, Ruttiger L, Habig K, Poths S, Bonin M, Knipper M, Schmidt WJ, Wilbertz J, Wolburg H, Laccone F, Riess O (2007) Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci 27:7418-7428.
Bolos M, Fernandez S, Torres-Aleman I (2010) Oral administration of a GSK3 inhibitor increases brain insulin-like growth factor I levels. J Biol Chem 285:17693-17700.
Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10 Suppl:S2-9.
Buckman JF, Hernandez H, Kress GJ, Votyakova TV, Pal S, Reynolds IJ (2001) MitoTracker labeling in primary neuronal and astrocytic cultures: influence of mitochondrial membrane potential and oxidants. J Neurosci Methods 104:165-176.
Burnett B, Li F, Pittman RN (2003) The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet 12:3195-3205.
Burnett BG, Pittman RN (2005) The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci U S A 102:4330-4335.
Butler R, Bates GP (2006) Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci 7:784-796.
Carmichael J, Sugars KL, Bao YP, Rubinsztein DC (2002) Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J Biol Chem 277:33791-33798.
Cashikar AG, Duennwald M, Lindquist SL (2005) A chaperone pathway in protein disaggregation. Hsp26 alters the nature of protein aggregates to facilitate reactivation by Hsp104. J Biol Chem 280:23869-23875.
Chai Y, Berke SS, Cohen RE, Paulson HL (2004) Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem 279:3605-3611.
Chai Y, Koppenhafer SL, Shoesmith SJ, Perez MK, Paulson HL (1999) Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet 8:673-682.
Chan HM, La Thangue NB (2001) p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci 114:2363-2373.
Chang WH, Tien CL, Chen TJ, Nukina N, Hsieh M (2009) Decreased protein synthesis of Hsp27 associated with cellular toxicity in a cell model of Machado-Joseph disease. Neurosci Lett 454:152-156.
Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, Lu RB, Gean PW, Chuang DM, Hong JS (2007) Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149:203-212.
Cong SY, Pepers BA, Roos RA, van Ommen GJ, Dorsman JC (2006) Small N-terminal mutant huntingtin fragments, but not wild type, are mainly present in monomeric form: Implications for pathogenesis. Exp Neurol 199:257-264.
Costa V, Giacomello M, Hudec R, Lopreiato R, Ermak G, Lim D, Malorni W, Davies KJ, Carafoli E, Scorrano L (2010) Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli. EMBO Mol Med 2:490-503.
Cowan KJ, Diamond MI, Welch WJ (2003) Polyglutamine protein aggregation and toxicity are linked to the cellular stress response. Hum Mol Genet 12:1377-1391.
Crossthwaite AJ, Hasan S, Williams RJ (2002) Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. J Neurochem 80:24-35.
Davis PK, Johnson GV (1999) The microtubule binding of Tau and high molecular weight Tau in apoptotic PC12 cells is impaired because of altered phosphorylation. J Biol Chem 274:35686-35692.
Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5:981-989.
Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S, Saudou F (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J Neurosci 27:3571-3583.
Du Y, Wooten MC, Wooten MW (2009) Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol Dis 35:302-310.
Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT (2009) Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease. FASEB J 23:2459-2466.
Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean O, Chneiweiss H, Benomar A, Lyon-Caen O, Julien J, Serdaru M, Penet C, Agid Y, Brice A (1996) Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 39:490-499.
Esmaeli-Azad B, McCarty JH, Feinstein SC (1994) Sense and antisense transfection analysis of tau function: tau influences net microtubule assembly, neurite outgrowth and neuritic stability. J Cell Sci 107 ( Pt 4):869-879.
Evert BO, Araujo J, Vieira-Saecker AM, de Vos RA, Harendza S, Klockgether T, Wullner U (2006) Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J Neurosci 26:11474-11486.
Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, Smith K, Kowall NW, Ratan RR, Luthi-Carter R, Hersch SM (2003) Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci 23:9418-9427.
Firdaus WJ, Wyttenbach A, Diaz-Latoud C, Currie RW, Arrigo AP (2006) Analysis of oxidative events induced by expanded polyglutamine huntingtin exon 1 that are differentially restored by expression of heat shock proteins or treatment with an antioxidant. FEBS J 273:3076-3093.
Fontaine-Lenoir V, Chambraud B, Fellous A, David S, Duchossoy Y, Baulieu EE, Robel P (2006) Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor. Proc Natl Acad Sci U S A 103:4711-4716.
Fortini ME (2007) Medicine. Anticipating trouble from gene transcription. Science 315:1800-1801.
Fowler HL (1984) Machado-Joseph-Azorean disease. A ten-year study. Arch Neurol 41:921-925.
Friedman MJ, Li S, Li XJ (2009) Activation of gene transcription by heat shock protein 27 may contribute to its neuronal protection. J Biol Chem 284:27944-27951.
Gao L, Cueto MA, Asselbergs F, Atadja P (2002) Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem 277:25748-25755.
Gaub P, Tedeschi A, Puttagunta R, Nguyen T, Schmandke A, Di Giovanni S (2010) HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death Differ 17:1392-1408.
Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, Cordelieres FP, De Mey J, MacDonald ME, Lessmann V, Humbert S, Saudou F (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127-138.
Giuliano P, De Cristofaro T, Affaitati A, Pizzulo GM, Feliciello A, Criscuolo C, De Michele G, Filla A, Avvedimento EV, Varrone S (2003) DNA damage induced by polyglutamine-expanded proteins. Hum Mol Genet 12:2301-2309.
Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895-899.
Gorman AM, Szegezdi E, Quigney DJ, Samali A (2005) Hsp27 inhibits 6-hydroxydopamine-induced cytochrome c release and apoptosis in PC12 cells. Biochem Biophys Res Commun 327:801-810.
Goswami A, Dikshit P, Mishra A, Nukina N, Jana NR (2006a) Expression of expanded polyglutamine proteins suppresses the activation of transcription factor NFkappaB. J Biol Chem 281:37017-37024.
Goswami A, Dikshit P, Mishra A, Mulherkar S, Nukina N, Jana NR (2006b) Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction. Biochem Biophys Res Commun 342:184-190.
Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, Ben-Haiem L, Jenkins NA, Copeland NG, Kakizuka A, Sharp AH, Ross CA, Mouton PR, Colomer V (2004) A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci 24:10266-10279.
Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424-2428.
Grunstein M (1997) Histone acetylation in chromatin structure and transcription. Nature 389:349-352.
Haacke A, Broadley SA, Boteva R, Tzvetkov N, Hartl FU, Breuer P (2006) Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3. Hum Mol Genet 15:555-568.
Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 24:6590-6599.
Harding AE (1982) The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the 'the Drew family of Walworth'. Brain 105:1-28.
Heng MY, Duong DK, Albin RL, Tallaksen-Greene SJ, Hunter JM, Lesort MJ, Osmand A, Paulson HL, Detloff PJ (2010) Early autophagic response in a novel knock-in model of Huntington disease. Hum Mol Genet 19:3702-3720.
Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A 100:2041-2046.
Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2:831-837.
Huuskonen J, Suuronen T, Nuutinen T, Kyrylenko S, Salminen A (2004) Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br J Pharmacol 141:874-880.
Iwata A, Riley BE, Johnston JA, Kopito RR (2005) HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 280:40282-40292.
Jardim LB, Silveira I, Pereira ML, Ferro A, Alonso I, do Ceu Moreira M, Mendonca P, Ferreirinha F, Sequeiros J, Giugliani R (2001) A survey of spinocerebellar ataxia in South Brazil - 66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease-causing mutations. J Neurol 248:870-876.
Jeong H, Then F, Melia TJ, Jr., Mazzulli JR, Cui L, Savas JN, Voisine C, Paganetti P, Tanese N, Hart AC, Yamamoto A, Krainc D (2009) Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137:60-72.
Jorgensen ND, Andresen JM, Pitt JE, Swenson MA, Zoghbi HY, Orr HT (2007) Hsp70/Hsc70 regulates the effect phosphorylation has on stabilizing ataxin-1. J Neurochem 102:2040-2048.
Jung J, Bonini N (2007) CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science 315:1857-1859.
Jung J, Xu K, Lessing D, Bonini NM (2009) Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet 18:4843-4852.
Kanai H, Sawa A, Chen RW, Leeds P, Chuang DM (2004) Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics J 4:336-344.
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, et al. (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221-228.
Kaytor MD, Burright EN, Duvick LA, Zoghbi HY, Orr HT (1997) Increased trinucleotide repeat instability with advanced maternal age. Hum Mol Genet 6:2135-2139.
Kim SJ, Kim TS, Hong S, Rhim H, Kim IY, Kang S (2003) Oxidative stimuli affect polyglutamine aggregation and cell death in human mutant ataxin-1-expressing cells. Neurosci Lett 348:21-24.
Kim WY, Horbinski C, Sigurdson W, Higgins D (2004) Proteasome inhibitors suppress formation of polyglutamine-induced nuclear inclusions in cultured postmitotic neurons. J Neurochem 91:1044-1056.
Koulich E, Nguyen T, Johnson K, Giardina C, D'Mello S (2001) NF-kappaB is involved in the survival of cerebellar granule neurons: association of IkappaBbeta [correction of Ikappabeta] phosphorylation with cell survival. J Neurochem 76:1188-1198.
Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T (2007) ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 14:230-239.
Kubodera T, Yokota T, Ohwada K, Ishikawa K, Miura H, Matsuoka T, Mizusawa H (2003) Proteolytic cleavage and cellular toxicity of the human alpha1A calcium channel in spinocerebellar ataxia type 6. Neurosci Lett 341:74-78.
La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77-79.
LaFevre-Bernt MA, Ellerby LM (2003) Kennedy's disease. Phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death. J Biol Chem 278:34918-34924.
Lam PY, Cadenas E (2008) Compromised proteasome degradation elevates neuronal nitric oxide synthase levels and induces apoptotic cell death. Arch Biochem Biophys 478:181-186.
Langley B, D'Annibale MA, Suh K, Ayoub I, Tolhurst A, Bastan B, Yang L, Ko B, Fisher M, Cho S, Beal MF, Ratan RR (2008) Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21(waf1/cip1) in cell cycle-independent neuroprotection. J Neurosci 28:163-176.
Lee DC, Mason CW, Goodman CB, Holder MS, Kirksey OW, Womble TA, Severs WB, Palm DE (2007) Hydrogen peroxide induces lysosomal protease alterations in PC12 cells. Neurochem Res 32:1499-1510.
Lee do H, Goldberg AL (2010) Hsp104 is essential for the selective degradation in yeast of polyglutamine expanded ataxin-1 but not most misfolded proteins generally. Biochem Biophys Res Commun 391:1056-1061.
Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28:2576-2588.
Li F, Macfarlan T, Pittman RN, Chakravarti D (2002) Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem 277:45004-45012.
Limprasert P, Nouri N, Heyman RA, Nopparatana C, Kamonsilp M, Deininger PL, Keats BJ (1996) Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats. Hum Mol Genet 5:207-213.
Maher P, Hanneken A (2005) The molecular basis of oxidative stress-induced cell death in an immortalized retinal ganglion cell line. Invest Ophthalmol Vis Sci 46:749-757.
Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12:1247-1252.
Manto MU (2005) The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 4:2-6.
Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, De Camilli P (2005) Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci U S A 102:12700-12705.
Marcora E, Kennedy MB (2010) The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-kappaB from the synapse to the nucleus. Hum Mol Genet 19:4373-4384.
Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, de Vries R, Arias E, Harris S, Sulzer D, Cuervo AM (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat Neurosci 13:567-576.
Mathis DJ, Oudet P, Wasylyk B, Chambon P (1978) Effect of histone acetylation on structure and in vitro transcription of chromatin. Nucleic Acids Res 5:3523-3547.
Matsumoto M, Yada M, Hatakeyama S, Ishimoto H, Tanimura T, Tsuji S, Kakizuka A, Kitagawa M, Nakayama KI (2004) Molecular clearance of ataxin-3 is regulated by a mammalian E4. EMBO J 23:659-669.
Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC (2010) Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133:93-104.
Mishra A, Godavarthi SK, Maheshwari M, Goswami A, Jana NR (2009) The ubiquitin ligase E6-AP is induced and recruited to aggresomes in response to proteasome inhibition and may be involved in the ubiquitination of Hsp70-bound misfolded proteins. J Biol Chem 284:10537-10545.
Miyata R, Hayashi M, Tanuma N, Shioda K, Fukatsu R, Mizutani S (2008) Oxidative stress in neurodegeneration in dentatorubral-pallidoluysian atrophy. J Neurol Sci 264:133-139.
Naito H, Oyanagi S (1982) Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral-pallidoluysian atrophy. Neurology 32:798-807.
Netravathi M, Pal PK, Purushottam M, Thennarasu K, Mukherjee M, Jain S (2009) Spinocerebellar ataxias types 1, 2 and 3: age adjusted clinical severity of disease at presentation correlates with size of CAG repeat lengths. J Neurol Sci 277:83-86.
Nucifora FC, Jr., Ellerby LM, Wellington CL, Wood JD, Herring WJ, Sawa A, Hayden MR, Dawson VL, Dawson TM, Ross CA (2003) Nuclear localization of a non-caspase truncation product of atrophin-1, with an expanded polyglutamine repeat, increases cellular toxicity. J Biol Chem 278:13047-13055.
Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575-621.
Palazzolo I, Burnett BG, Young JE, Brenne PL, La Spada AR, Fischbeck KH, Howell BW, Pennuto M (2007) Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum Mol Genet 16:1593-1603.
Palhan VB, Chen S, Peng GH, Tjernberg A, Gamper AM, Fan Y, Chait BT, La Spada AR, Roeder RG (2005) Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci U S A 102:8472-8477.
Pandolfo M (2008) Drug Insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol 4:86-96.
Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci 5:731-736.
Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19:333-344.
Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6:729-742.
Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, Yang S, Hong JS (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res 134:162-169.
Perez-Severiano F, Escalante B, Vergara P, Rios C, Segovia J (2002) Age-dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington's disease mutation. Brain Res 951:36-42.
Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN (1998) Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 143:1457-1470.
Pias EK, Ekshyyan OY, Rhoads CA, Fuseler J, Harrison L, Aw TY (2003) Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells. J Biol Chem 278:13294-13301.
Piccioli P, Porcile C, Stanzione S, Bisaglia M, Bajetto A, Bonavia R, Florio T, Schettini G (2001) Inhibition of nuclear factor-kappaB activation induces apoptosis in cerebellar granule cells. J Neurosci Res 66:1064-1073.
Puranam KL, Wu G, Strittmatter WJ, Burke JR (2006) Polyglutamine expansion inhibits respiration by increasing reactive oxygen species in isolated mitochondria. Biochem Biophys Res Commun 341:607-613.
Qin ZH, Wang Y, Kegel KB, Kazantsev A, Apostol BL, Thompson LM, Yoder J, Aronin N, DiFiglia M (2003) Autophagy regulates the processing of amino terminal huntingtin fragments. Hum Mol Genet 12:3231-3244.
Ranen NG, Stine OC, Abbott MH, Sherr M, Codori AM, Franz ML, Chao NI, Chung AS, Pleasant N, Callahan C, et al. (1995) Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet 57:593-602.
Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fischbeck KH (2009) Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 18:27-42.
Rasmussen A, De Biase I, Fragoso-Benitez M, Macias-Flores MA, Yescas P, Ochoa A, Ashizawa T, Alonso ME, Bidichandani SI (2007) Anticipation and intergenerational repeat instability in spinocerebellar ataxia type 17. Ann Neurol 61:607-610.
Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107-1117.
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585-595.
Reijonen S, Kukkonen JP, Hyrskyluoto A, Kivinen J, Kairisalo M, Takei N, Lindholm D, Korhonen L (2010) Downregulation of NF-kappaB signaling by mutant huntingtin proteins induces oxidative stress and cell death. Cell Mol Life Sci 67:1929-1941.
Reina CP, Zhong X, Pittman RN (2010) Proteotoxic stress increases nuclear localization of ataxin-3. Hum Mol Genet 19:235-249.
Ring RH, Alder J, Fennell M, Kouranova E, Black IB, Thakker-Varia S (2006) Transcriptional profiling of brain-derived-neurotrophic factor-induced neuronal plasticity: a novel role for nociceptin in hippocampal neurite outgrowth. J Neurobiol 66:361-377.
Rodrigues AJ, do Carmo Costa M, Silva TL, Ferreira D, Bajanca F, Logarinho E, Maciel P (2010) Absence of ataxin-3 leads to cytoskeletal disorganization and increased cell death. Biochim Biophys Acta 1803:1154-1163.
Rosenberg RN (1992) Machado-Joseph disease: an autosomal dominant motor system degeneration. Mov Disord 7:193-203.
Rosenberg RN (1995) Autosomal dominant cerebellar phenotypes: the genotype has settled the issue. Neurology 45:1-5.
Roze E, Betuing S, Deyts C, Marcon E, Brami-Cherrier K, Pages C, Humbert S, Merienne K, Caboche J (2008) Mitogen- and stress-activated protein kinase-1 deficiency is involved in expanded-huntingtin-induced transcriptional dysregulation and striatal death. FASEB J 22:1083-1093.
Rub U, de Vos RA, Brunt ER, Sebesteny T, Schols L, Auburger G, Bohl J, Ghebremedhin E, Gierga K, Seidel K, den Dunnen W, Heinsen H, Paulson H, Deller T (2006) Spinocerebellar ataxia type 3 (SCA3): thalamic neurodegeneration occurs independently from thalamic ataxin-3 immunopositive neuronal intranuclear inclusions. Brain Pathol 16:218-227.
Ryu H, Lee J, Olofsson BA, Mwidau A, Dedeoglu A, Escudero M, Flemington E, Azizkhan-Clifford J, Ferrante RJ, Ratan RR (2003) Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci U S A 100:4281-4286.
Ryu J, Cho S, Park BC, Lee do H (2010) Oxidative stress-enhanced SUMOylation and aggregation of ataxin-1: Implication of JNK pathway. Biochem Biophys Res Commun 393:280-285.
Saha RN, Pahan K (2006) HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ 13:539-550.
Sarkar S, Krishna G, Imarisio S, Saiki S, O'Kane CJ, Rubinsztein DC (2008) A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum Mol Genet 17:170-178.
Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M, Cook LJ, Rubinsztein DC (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170:1101-1111.
Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, Takahashi M, Matsuura T, Flanigan KM, Iwasaki S, Ishino F, Saito Y, Murayama S, Yoshida M, Hashizume Y, Takahashi Y, Tsuji S, Shimizu N, Toda T, Ishikawa K, Mizusawa H (2009a) Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet 85:544-557.
Sato T, Miura M, Yamada M, Yoshida T, Wood JD, Yazawa I, Masuda M, Suzuki T, Shin RM, Yau HJ, Liu FC, Shimohata T, Onodera O, Ross CA, Katsuki M, Takahashi H, Kano M, Aosaki T, Tsuji S (2009b) Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice. Hum Mol Genet 18:723-736.
Sayre LM, Perry G, Smith MA (2008) Oxidative stress and neurotoxicity. Chem Res Toxicol 21:172-188.
Schols L, Bauer P, Schmidt T, Schulte T, Riess O (2004) Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3:291-304.
Silveira I, Lopes-Cendes I, Kish S, Maciel P, Gaspar C, Coutinho P, Botez MI, Teive H, Arruda W, Steiner CE, Pinto-Junior W, Maciel JA, Jerin S, Sack G, Andermann E, Sudarsky L, Rosenberg R, MacLeod P, Chitayat D, Babul R, Sequeiros J, Rouleau GA (1996) Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology 46:214-218.
Song C, Perides G, Liu YF (2002) Expression of full-length polyglutamine-expanded Huntingtin disrupts growth factor receptor signaling in rat pheochromocytoma (PC12) cells. J Biol Chem 277:6703-6707.
Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17:377-382.
Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739-743.
Stetler RA, Cao G, Gao Y, Zhang F, Wang S, Weng Z, Vosler P, Zhang L, Signore A, Graham SH, Chen J (2008) Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. J Neurosci 28:13038-13055.
Sun F, Anantharam V, Zhang D, Latchoumycandane C, Kanthasamy A, Kanthasamy AG (2006) Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Neurotoxicology 27:807-815.
Suzuki-Mizushima Y, Gohda E, Okamura T, Kanasaki K, Yamamoto I (2002) Enhancement of NGF- and cholera toxin-induced neurite outgrowth by butyrate in PC12 cells. Brain Res 951:209-217.
Swami M, Hendricks AE, Gillis T, Massood T, Mysore J, Myers RH, Wheeler VC (2009) Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum Mol Genet 18:3039-3047.
Tanida I, Ueno T, Kominami E (2004) Human light chain 3/MAP1LC3B is cleaved at its carboxyl-terminal Met121 to expose Gly120 for lipidation and targeting to autophagosomal membranes. J Biol Chem 279:47704-47710.
Taylor JP, Hardy J, Fischbeck KH (2002) Toxic proteins in neurodegenerative disease. Science 296:1991-1995.
Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L, et al. (1995) Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378:403-406.
Tsai HF, Tsai HJ, Hsieh M (2004) Full-length expanded ataxin-3 enhances mitochondrial-mediated cell death and decreases Bcl-2 expression in human neuroblastoma cells. Biochem Biophys Res Commun 324:1274-1282.
Tsai HF, Lin SJ, Li C, Hsieh M (2005) Decreased expression of Hsp27 and Hsp70 in transformed lymphoblastoid cells from patients with spinocerebellar ataxia type 7. Biochem Biophys Res Commun 334:1279-1286.
Tsirigotis M, Baldwin RM, Tang MY, Lorimer IA, Gray DA (2008) Activation of p38MAPK contributes to expanded polyglutamine-induced cytotoxicity. PLoS One 3:e2130.
Uo T, Veenstra TD, Morrison RS (2009) Histone deacetylase inhibitors prevent p53-dependent and p53-independent Bax-mediated neuronal apoptosis through two distinct mechanisms. J Neurosci 29:2824-2832.
van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC, Scheffer H, Brunt ER, Ippel PF, Maat-Kievit JA, Dooijes D, Notermans NC, Lindhout D, Knoers NV, Kremer HP (2002) Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology 58:702-708.
van Tijn P, de Vrij FM, Schuurman KG, Dantuma NP, Fischer DF, van Leeuwen FW, Hol EM (2007) Dose-dependent inhibition of proteasome activity by a mutant ubiquitin associated with neurodegenerative disease. J Cell Sci 120:1615-1623.
Varma H, Cheng R, Voisine C, Hart AC, Stockwell BR (2007) Inhibitors of metabolism rescue cell death in Huntington's disease models. Proc Natl Acad Sci U S A 104:14525-14530.
Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26:1-14.
Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, Wanker EE (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12:1393-1407.
Wang H, Lim PJ, Karbowski M, Monteiro MJ (2009) Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 18:737-752.
Wang H, Lim PJ, Yin C, Rieckher M, Vogel BE, Monteiro MJ (2006) Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Hum Mol Genet 15:1025-1041.
Wang H, Jia N, Fei E, Wang Z, Liu C, Zhang T, Fan J, Wu M, Chen L, Nukina N, Zhou J, Wang G (2007a) p45, an ATPase subunit of the 19S proteasome, targets the polyglutamine disease protein ataxin-3 to the proteasome. J Neurochem 101:1651-1661.
Wang HL, He CY, Chou AH, Yeh TH, Chen YL, Li AH (2007b) Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-kappaB p65 and impairs NF-kappaB activity by inhibiting proteasome activity of cerebellar neurons. Cell Signal 19:573-581.
Wang H-H (2007) Evaluation of therapeutic effect of valproic acid in polyglutamine-expanded cell and animal models. Dept of LifeScience, NTNU, Taiwan, Taipei, Master's thesis
Wen FC, Li YH, Tsai HF, Lin CH, Li C, Liu CS, Lii CK, Nukina N, Hsieh M (2003) Down-regulation of heat shock protein 27 in neuronal cells and non-neuronal cells expressing mutant ataxin-3. FEBS Lett 546:307-314.
Williams AJ, Knutson TM, Colomer Gould VF, Paulson HL (2009) In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis. Neurobiol Dis 33:342-353.
Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo AP, Rubinsztein DC (2002) Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet 11:1137-1151.
Wyttenbach A, Carmichael J, Swartz J, Furlong RA, Narain Y, Rankin J, Rubinsztein DC (2000) Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Proc Natl Acad Sci U S A 97:2898-2903.
Xie Y, Hayden MR, Xu B (2010) BDNF overexpression in the forebrain rescues Huntington's disease phenotypes in YAC128 mice. J Neurosci 30:14708-14718.
Yamagishi N, Goto K, Nakagawa S, Saito Y, Hatayama T (2010) Hsp105 reduces the protein aggregation and cytotoxicity by expanded-polyglutamine proteins through the induction of Hsp70. Exp Cell Res 316:2424-2433.
Yen H-H (2010) Establishment of and inducible cell model system for spinocerebellar ataxia type 3 potential drug screen. Dept of LifeScience, NTNU, Taiwan, Taipei, Master's thesis
Yoshizawa T, Yamagishi Y, Koseki N, Goto J, Yoshida H, Shibasaki F, Shoji S, Kanazawa I (2000) Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Hum Mol Genet 9:69-78.
Young JE, Gouw L, Propp S, Sopher BL, Taylor J, Lin A, Hermel E, Logvinova A, Chen SF, Chen S, Bredesen DE, Truant R, Ptacek LJ, La Spada AR, Ellerby LM (2007) Proteolytic cleavage of ataxin-7 by caspase-7 modulates cellular toxicity and transcriptional dysregulation. J Biol Chem 282:30150-30160.
Yu YC, Kuo CL, Cheng WL, Liu CS, Hsieh M (2009) Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease. J Neurosci Res 87:1884-1891.
Zaveri NT, Waleh N, Toll L (2006) Regulation of the prepronociceptin gene and its effect on neuronal differentiation. Gene 384:27-36.
Zhao K, Luo G, Giannelli S, Szeto HH (2005) Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines. Biochem Pharmacol 70:1796-1806.
Zourlidou A, Gidalevitz T, Kristiansen M, Landles C, Woodman B, Wells DJ, Latchman DS, de Belleroche J, Tabrizi SJ, Morimoto RI, Bates GP (2007) Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation. Hum Mol Genet 16:1078-1090.
Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 293:493-498.