Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

Matilla-Dueñas A, Goold R, Giunti P (2006) Molecular pathogenesis of spinocerebellar ataxias. Brain 129:1357–1370 Tsuji S, Onodera O, Goto J, Nishizawa M (2008) Sporadic ataxias in Japan—a population-based epidemiological study. Cerebellum 7:189–197 Schols L, Peters S, Szymanski S, Kruger R, Lange S, Hardt C et al (2000) Extrapyramidal motor signs in degenerative ataxias. Arch Neurol 57:1495–1500 Riess O, Rub U, Pastore A, Bauer P, Schols L (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7:125–137 Wang YG, Du J, Wang JL, Chen J, Chen C, Luo YY et al (2009) Six cases of SCA3/MJD patients that mimic hereditary spastic paraplegia in clinic. J Neurol Sci 285:121–124 Gan SR, Zhao K, Wu ZY, Wang N, Murong SX (2009) Chinese patients with Machado-Joseph disease presenting with complicated hereditary spastic paraplegia. Eur J Neurol 16:953–956 Lukas C, Hahn HK, Bellenberg B, Hellwig K, Globas C, Schimrigk SK et al (2008) Spinal cord atrophy in spinocerebellar ataxia type 3 and 6: impact on clinical disability. J Neurol 255:1244–1249 Tan EK, Tong J, Pavanni R, Wong MC, Zhao Y (2007) Genetic analysis of SCA 2 and 3 repeat expansions in essential tremor and atypical Parkinsonism. Mov Disord 22:1971–1974 Reimold M, Globas C, Gleichmann M, Schulze M, Gerloff C, Bares R et al (2006) Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomography. Mov Disord 21:1667–1673 Friedman JH, Fernandez HH, Sudarsky LR (2003) REM behavior disorder and excessive daytime somnolence in Machado–Joseph disease (SCA-3). Mov Disord 18:1520–1522 Pradhan C, Yashavantha BS, Pal PK, Sathyaprabha TN (2008) Spinocerebellar ataxias type 1, 2 and 3: a study of heart rate variability. Acta Neurol Scand 117:337–342 van de Warrenburg BP, Notermans NC, Schelhaas HJ, van Alfen N, Sinke RJ, Knoers NV et al (2004) Peripheral nerve involvement in spinocerebellar ataxias. Arch Neurol 61:257–261 Burk K, Globas C, Bosch S, Klockgether T, Zuhlke C, Daum I et al (2003) Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J Neurol 250:207–211 Gupta SN, Marks HG (2008) Spinocerebellar ataxia type 7 mimicking Kearns–Sayre syndrome: a clinical diagnosis is desirable. J Neurol Sci 264:173–176 Wardle M, Morris HR, Robertson NP (2009) Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: a systematic review. Mov Disord 24:1636–1640 Matilla-Dueñas A (2008) The highly heterogeneous spinocerebellar ataxias: from genes to targets for therapeutic intervention. Cerebellum 7:97–100 Holmes SE, O'Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C et al (1999) Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat Genet 23:391–392 Wakamiya M, Matsuura T, Liu Y, Schuster GC, Gao R, Xu W et al (2006) The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10. Neurology 67:607–613 Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ et al (2009) RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet 5:e1000600 Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC et al (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38:184–190 Houlden H, Johnson J, Gardner-Thorpe C, Lashley T, Hernandez D, Worth P et al (2007) Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39:1434–1436 Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D et al (2006) Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet 38:447–451 Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D et al (2003) Missense mutations in the regulatory domain of PKCgamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 72:839–849 Yabe I, Sasaki H, Chen DH, Raskind WH, Bird TD, Yamashita I et al (2003) Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch Neurol 60:1749–1751 van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR et al (2007) Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 3:e108 van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I et al (2003) A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebral ataxia. Am J Hum Genet 72:191–199 Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G (2009) Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. J Neurosci 29:9244–9254 Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217–247 Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–S17 Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19:148–154 McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J et al (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9:2197–2202 Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J et al (2002) Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol 51:302–310 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 Park Y, Hong S, Kim SJ, Kang S (2005) Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product. Mol Cells 19:23–30 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 USA 102:12700–12705 Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM (2004) Caspase activation inhibits proteasome function during apoptosis. Mol Cell 14:81–93 Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT et al (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 10:1511–1518 Bonini NM (2002) Chaperoning brain degeneration. Proc Nat Acad Sci USA 99:16407–16411 Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU (2002) Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Nat Acad Sci USA 99:16412–16418 He C, Klionsky DJ (2009) Regulation Mechanisms and Signaling Pathways of Autophagy. Annu Rev Genet (in press) Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS et al (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Nat Acad Sci USA 102:13135–13140 Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG et al (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 Helmlinger D, Tora L, Devys D (2006) Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet 22:562–570 Matilla A, Koshy BT, Cummings CJ, Isobe T, Orr HT, Zoghbi HY (1997) The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389:974–978 Okazawa H, Rich T, Chang A, Lin X, Waragai M, Kajikawa M et al (2002) Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 34:701–713 Tsai CC, Kao HY, Mitzutani A, Banayo E, Rajan H, McKeown M et al (2004) Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc Nat Acad Sci USA 101:4047–4052 Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP et al (2005) Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J 24:3339–3351 Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF et al (2005) The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/senseless proteins. Cell 122:633–644 Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD et al (2006) ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127:1335–1347 Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N et al (2006) RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 127:697–708 Goold R, Hubank M, Hunt A, Holton J, Menon RP, Revesz T et al (2007) Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1. Hum Mol Genet 16:2122–2134 Matilla-Dueñas A, Goold R, Giunti P (2008) Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum 7:106–114 Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S et al (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26:29–36 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 Zhang S, Xu L, Lee J, Xu T (2002) Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell 108:45–56 Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C et al (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13:1257–1265 Friedman MJ, Shah AG, Fang ZH, Ward EG, Warren ST, Li S et al (2007) Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration. Nat Neurosci 10:1519–1528 Matilla A, Radrizzani M (2005) The Anp32 family of proteins containing leucine-rich repeats. Cerebellum 4:7–18 La Spada AR, Fu Y, Sopher BL, Libby RT, Wang X, Li LY et al (2001) Polyglutamine-expanded ataxin-7 antagonizes crx function and induces cone-rod dystrophy in a mouse model of sca7. Neuron 31:913–927 Kouzarides T (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19:1176–1179 Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL et al (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743 McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KH (2001) Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Nat Acad Sci USA 98:15179–15184 Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E et al (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Nat Acad Sci USA 100:2041–2046 Clark HB, Burright EN, Yunis WS, Larson S, Wilcox C, Hartman B et al (1997) Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations. J Neurosci 17:7385–7395 Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT (2004) Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet 13:2535–2543 Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R et al (2000) mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288:1832–1835 Ikeda Y, Daughters RS, Ranum LP (2008) Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. Cerebellum 7:150–158 Worth PF, Houlden H, Giunti P, Davis MB, Wood NW (2000) Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nat Genet 24:214–215 Corral J, Genis D, Banchs I, San Nicolas H, Armstrong J, Volpini V (2005) Giant SCA8 alleles in nine children whose mother has two moderately large ones. Ann Neurol 57:549–553 Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY (2000) Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 3:157–163 Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP et al (2009) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 29:9148–9162 Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C et al (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–69 Pietrobon D (2002) Calcium channels and channelopathies of the central nervous system. Mol Neurobiol 25:31–50 Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, Zong S et al (2007) Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Mol Cell Neurosci 34:261–270 Adachi N, Kobayashi T, Takahashi H, Kawasaki T, Shirai Y, Ueyama T et al (2008) Enzymological analysis of mutant protein kinase Cgamma causing spinocerebellar ataxia type 14 and dysfunction in Ca2+ homeostasis. J Biol Chem 283:19854–19863 Lipinski MM, Yuan J (2004) Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharm 4:85–90 Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, Yuan J (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22:623–633 Chou AH, Yeh TH, Kuo YL, Kao YC, Jou MJ, Hsu CY et al (2006) Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-x(L). Neurobiol Dis 21:333–345 Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY et al (2006) Polyglutamine-expanded ataxin-7 activates mitochondrial apoptotic pathway of cerebellar neurons by upregulating Bax and downregulating Bcl-x(L). Cell Signal 18:541–552 Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH et al (2003) Interaction of Akt-phosphorylated ataxin-1 with 14–3–3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457–468 van de Warrenburg BP, Hendriks H, Durr A, van Zuijlen MC, Stevanin G, Camuzat A et al (2005) Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch–French cohort. Ann Neurol 57:505–512 Albrecht M, Golatta M, Wullner U, Lengauer T (2004) Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem 271:3155–3170 He W, Parker R (2000) Functions of Lsm proteins in mRNA degradation and splicing. Curr Opin Cell Biol 12:346–350 Shibata H, Huynh DP, Pulst SM (2000) A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet 9:1303–1313 Jin Y, Suzuki H, Maegawa S, Endo H, Sugano S, Hashimoto K et al (2003) A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG. EMBO J 22:905–912 Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K et al (2000) Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 26:191–194 Lin X, Ashizawa T (2005) Recent progress in spinocerebellar ataxia type-10 (SCA10). Cerebellum 4:37–42 Coates JC (2003) Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol 13:463–471 Sontag E (2001) Protein phosphatase 2A: the Trojan horse of cellular signaling. Cell Signal 13:7–16 Lim J, Lu KP (2005) Pinning down phosphorylated tau and tauopathies. Biochim Biophys Acta 1739:311–322 Waters MF, Pulst SM (2008) Sca13. Cerebellum 7:165–169 Newton AC (2001) Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101:2353–2364 Schrenk K, Kapfhammer JP, Metzger F (2002) Altered dendritic development of cerebellar Purkinje cells in slice cultures from protein kinase Cgamma-deficient mice. Neuroscience 110:675–689 Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S (1993) PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75:1263–1271 Verbeek DS, Goedhart J, Bruinsma L, Sinke RJ, Reits EA (2008) PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling. J Cell Sci 121:2339–2349 Wang Q, Bardgett ME, Wong M, Wozniak DF, Lou J, McNeil BD et al (2002) Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 35:25–38 Shakkottai VG, Xiao M, Xu L, Wong M, Nerbonne JM, Ornitz DM et al (2009) FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis 33:81–88 Ishikawa K, Toru S, Tsunemi T, Li M, Kobayashi K, Yokota T et al (2005) An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5′ untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains. Am J Hum Genet 77:280–296 Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF et al (1996) Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 59:392–399 Manto M, Marmolino D (2009) Cerebellar ataxias. Curr Opin Neurol 22:419–429 Trujillo-Martin MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R (2009) Effectiveness and safety of treatments for degenerative ataxias: a systematic review. Mov Disord 24:1111–1124 Watase K, Gatchel JR, Sun Y, Emamian E, Atkinson R, Richman R et al (2007) Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med 4:e182 Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT et al (2004) RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 10:816–820 Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22 Chan HY, Warrick JM, Gray-Board GL, Paulson HL, Bonini NM (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9:2811–2820 Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N et al (2000) Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc Nat Acad Sci USA 97:6739–6744 Sanchez I, Mahlke C, Yuan J (2003) Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421:373–379 Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I (2002) Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol Dis 10:88–99 Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H et al (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10:148–154 Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S et al (2002) Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc Nat Acad Sci USA 99:16400–16406 Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE, Roark M et al (2005) A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Nat Acad Sci USA 102:892–897 Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L (2004) Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 10:402–405 Rimoldi M, Servadio A, Zimarino V (2001) Analysis of heat shock transcription factor for suppression of polyglutamine toxicity. Brain Res Bull 56:353–362 Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918 Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW et al (2002) Therapeutic effects of cystamine in a murine model of Huntington's disease. J Neurosci 22:8942–8950 Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R et al (2002) Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 8:143–149 Shults CW (2003) Coenzyme Q10 in neurodegenerative diseases. Curr Med Chem 10:1917–1921 Ryu H, Rosas HD, Hersch SM, Ferrante RJ (2005) The therapeutic role of creatine in Huntington's disease. Pharmacol Ther 108:193–207 Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC (2002) Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Nat Acad Sci USA 99:10671–10676 Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM et al (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399:263–267 Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S et al (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801 Lesort M, Lee M, Tucholski J, Johnson GV (2003) Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem 278:3825–3830 Gauthier S (2009) Dimebon improves cognitive function in people with mild to moderate Alzheimer's disease. Evid Based Ment Health 12:21 Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C (2009) Therapeutic interventions for disease progression in Huntington's disease. Cochrane Database Syst Rev CD006455 Bordet T, Buisson B, Michaud M, Drouot C, Galea P, Delaage P et al (2007) Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther 322:709–720 Strupp M, Kalla R, Glasauer S, Wagner J, Hufner K, Jahn K et al (2008) Aminopyridines for the treatment of cerebellar and ocular motor disorders. Prog Brain Res 171:535–541 Dokmanovic M, Marks PA (2005) Prospects: Histone deacetylase inhibitors. J Cell Biochem 96:293–304 Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E, Burnett R et al (2008) The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc Natl Acad Sci USA 105:15564–15569 Naoi M, Maruyama W, Yi H, Inaba K, Akao Y, Shamoto-Nagai M (2009) Mitochondria in neurodegenerative disorders: regulation of the redox state and death signaling leading to neuronal death and survival. J Neural Transm (in press) Gatchel JR, Watase K, Thaller C, Carson JP, Jafar-Nejad P, Shaw C et al (2008) The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. Proc Nat Acad Sci USA 105:1291–1296 Fernandez AM, Carro EM, Lopez-Lopez C, Torres-Aleman I (2005) Insulin-like growth factor I treatment for cerebellar ataxia: Addressing a common pathway in the pathological cascade? Brain Res Rev 50:134–141 Leinninger GM, Feldman EL (2005) Insulin-like growth factors in the treatment of neurological disease. Endocr Devel 9:135–159 Gage FH (2002) Neurogenesis in the adult brain. J Neurosci 22:612–613 Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C et al (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720 Schmitz-Hubsch T, Giunti P, Stephenson DA, Globas C, Baliko L, Sacca F et al (2008) SCA Functional Index: a useful compound performance measure for spinocerebellar ataxia. Neurology 71:486–492 Lastres-Becker I, Rub U, Auburger G (2008) Spinocerebellar ataxia 2 (SCA2). Cerebellum 7:115–124 Garden GA, La Spada AR (2008) Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration. Cerebellum 7:138–149 Higgins JJ, Pho LT, Ide SE, Nee LE, Polymeropoulos MH (1997) Evidence for a new spinocerebellar ataxia locus. Mov Disord 12:412–417 Johnson J, Wood N, Giunti P, Houlden H (2008) Clinical and genetic analysis of spinocerebellar ataxia type 11. Cerebellum 7:159–164 Miyoshi Y, Yamada T, Tanimura M, Taniwaki T, Arakawa K, Ohyagi Y et al (2001) A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1. Neurology 57:96–100 Stevanin G, Brice A (2008) Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4). Cerebellum 7:170–178 Devos D, Schraen-Maschke S, Vuillaume I, Dujardin K, Naze P, Willoteaux C et al (2001) Clinical features and genetic analysis of a new form of spinocerebellar ataxia. Neurology 56:234–238 Verbeek DS, Schelhaas JH, Ippel EF, Beemer FA, Pearson PL, Sinke RJ (2002) Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21–q21. Hum Genet 111:388–393 Schelhaas HJ, van de Warrenburg BP (2005) Clinical, psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19). Cerebellum 4:51–54 Knight MA, Hernandez D, Diede SJ, Dauwerse HG, Rafferty I, van de Leemput J et al (2008) A duplication at chromosome 11q12.2–11q12.3 is associated with spinocerebellar ataxia type 20. Hum Mol Genet 17:3847–3853 Delplanque J, Devos D, Vuillaume I, De Becdelievre A, Vangelder E, Maurage CA et al (2008) Slowly progressive spinocerebellar ataxia with extrapyramidal signs and mild cognitive impairment (SCA21). Cerebellum 7:179–183 Chung MY, Lu YC, Cheng NC, Soong BW (2003) A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21–q23. Brain 126:1293–1299 Verbeek DS (2009) Spinocerebellar ataxia type 23: a genetic update. Cerebellum 8:104–107 Stevanin G, Broussolle E, Streichenberger N, Kopp N, Brice A, Durr A (2005) Spinocerebellar ataxia with sensory neuropathy (SCA25). Cerebellum 4:58–61 Yu GY, Howell MJ, Roller MJ, Xie TD, Gomez CM (2005) Spinocerebellar ataxia type 26 maps to chromosome 19p13.3 adjacent to SCA6. Ann Neurol 57:349–354 Mariotti C, Brusco A, Di Bella D, Cagnoli C, Seri M, Gellera C et al (2008) Spinocerebellar ataxia type 28: a novel autosomal dominant cerebellar ataxia characterized by slow progression and ophthalmoparesis. Cerebellum 7:184–188 Dudding TE, Friend K, Schofield PW, Lee S, Wilkinson IA, Richards RI (2004) Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology 63:2288–2292 Storey E, Bahlo M, Fahey M, Sisson O, Lueck CJ, Gardner RJ (2009) A new dominantly inherited pure cerebellar ataxia, SCA 30. J Neurol Neurosurg Psychiatry 80:408–411 Tsuji S (2002) Dentatorubral-pallidoluysian atrophy: clinical aspects and molecular genetics. Adv Neurol 89:231–239 Genis D, Ferrer I, Sole JV, Corral J, Volpini V, San Nicolas H et al (2009) A kindred with cerebellar ataxia and thermoanalgesia. J Neurol Neurosurg Psychiatry 80:518–523