臺灣博碩士論文加值系統

第三型脊髓小腦萎縮症的主要病因為 ataxin-3 (ATXN3)基因上 CAG 序列的過度
重複，導致突變 ATXN3 蛋白質的形成，此突變蛋白會經過鈣蛋白酶水解機制產
生小分子的毒性片段，目前已有許多文獻證實，這些毒性片段會引發毒性聚集物
的形成，堆積在神經細胞中，並造成神經毒性。直至今日，少有治療方法著重在
控制這些毒性片段的形成。此篇研究的目標是藉由追蹤毒性片段形成的複雜機制，
進而從中發展對第三型脊髓小腦萎縮症的替代治療對策。我們最初的研究利用人
類胚胎腎細胞 (HEK-293T-84Q-eGFP)模型，觀察到正丁烯基苯酞能夠減少在第
三型脊髓小腦萎縮症中毒性片段的生成量。除了細胞模型外，我們還使用了第三
型脊髓小腦萎縮症的基因轉殖鼠模型，藉由每週測試步伐穩定性、與 動作協調性，
發現每日餵食定量正丁烯基苯酞可改善其行為與平衡的能力。為了找出正丁烯基
苯酞藥物對此疾病的相關機制，我們使用微陣列分析技術，發現犬尿胺酸代謝在
毒性片段之生成與調控扮演重要角色。我們也證明了正丁烯基苯酞的功能在於調
節犬尿胺酸代謝的前期途徑，降低色胺酸 2,3-雙氧化酶 (TDO2)的表現，減少喹
啉酸的產生；隨著喹啉酸的減少，影響了神經細胞內的鈣離子濃度，使得鈣蛋白
酶無法被活化，進而減少了毒性片段和相關神經毒性的生成。本研究確立了正丁
烯基苯酞與犬尿胺酸代謝途徑之間的關聯性，同時也提供了對於此神經退化性疾
病的潛力治療對策。
關鍵字：第三型脊髓小腦萎縮症、正丁烯基苯酞、色胺酸 2,3-雙氧化酶、喹啉酸

Spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) is characterized by the repetition of a CAG codon in the ataxin-3 gene (ATXN3), which leads to the formation of an elongated mutant ATXN3 protein that can neither be denatured nor undergo proteolysis in the normal manner. This abnormal proteolysis leads to the accumulation of cleaved fragments, which have been identified as toxic and further they act as a seed for more aggregate formation, thereby increasing toxicity in neuronal cells. To date, there have been few studies or treatment strategies that have focused on controlling toxic fragment formation. The aim of this study is to develop a potential treatment strategy for addressing the complications of toxic fragment formation and to provide an alternative treatment strategy for SCA3. Our preliminary data on anti-aggregation and toxic fragment formation using an HEK (human embryonic kidney cells) 293T-84Q-eGFP (green fluorescent protein) cell model identified n-butylidenephthalide (n-BP) as a potential drug treatment for SCA3. n-BP decreased toxic fragment formation in both SCA3 cell and animal models. Moreover, results showed that n-BP can improve gait, motor coordination, and activity in SCA3 mice. To comprehend the molecular basis behind the control of toxic fragment formation, we used microarray analysis to identify tryptophan metabolism as a major player in controlling the fate of mutant ATXN3 aggregates. We also demonstrated that n-BP functions by regulating the early part of the kynurenine pathway through the downregulation of tryptophan 2, 3-dioxygenase (TDO2), which decreases the downstream neurotoxic product, quinolinic acid (QA). In addition, through the control of TDO2, n-BP also decreases active calpain levels, an important enzyme involved in the proteolysis of mutant ATXN3, thereby decreasing toxic fragment formation and associated neurotoxicity. Collectively, these findings indicate a correlation between n-BP, TDO2, QA, calpain, and toxic fragment formation. Thus, this study contributes to a better understanding of the molecular interactions involved in SCA3, and provides a novel potential treatment strategy for this neurodegenerative disease.
Key words: Spinocerebellar ataxia type 3, Tryptophan 2,3 dioxygenase, Quinolinic acid, Toxic fragment, Mutant ataxin 3

List of contents
Acknowledgements………………………………………………………………………………...........i
Mandarin Abstract……………………………………………………………………………................ii
English Abstract………………………………………………………………………………............... iii
List of contents…………………………………..………………………………………………............iv
Brief overview of the study and the thesis...................................................................x
Chapter 1: Introduction.......................................................................................................2
1. Polyglutamine Diseases..................................................................................................2
1.1. Categorization of Polyglutamine Diseases Based on its Genetics and Molecular Effects...................................................................................................................2
1.2. Epidemiology and Symptoms of Polyglutamine Diseases...........................7
1.3. Rationale behind interest in Polyglutamine diseases...................................12
2. Spinocerebellar ataxia 3...........................................................................................12
2.1. Genetics behind SCA3...............................................................................................13
2.2. Molecular effects behind SCA3.............................................................................14
2.2.1. Aggregation and Toxicity.....................................................................................14
2.3. Symptoms of SCA3.....................................................................................................16
2.4. Epidemiology of SCA3...............................................................................................16
2.5. Rationale behind interest in SCA3........................................................................17
2.6. Aim of this study..........................................................................................................18
2.7. Specific Objectives......................................................................................................18
3. Identification of potential models for studying SCA3..................................18
3.1. Review of literature - Cell models........................................................................18
3.1.1. Cell lines available in the market with personalized transfections......19
3.1.2. Direct Primary cell culture from mouse models and human patient..19
3.1.3. Reprogramming of primary cell culture from mouse and human patients ...................................................................................................................................................20
3.2. Rationale behind the choice of our cell model and aim behind the use of cell model......................................................................................................................................20
3.3. Objectives......................................................................................................................21
3.4. Cell model studies: HEK293T- pEGFP-C1-Ataxin3Q84................................21
3.4.1. Experimental setup to confirm the functionality of the cell model.....21
a. Cells.....................................................................................................................................21
b. Isogenic HEK 293T cell lines for 84Q-eGFP..........................................................21
c. Flow cytometry................................................................................................................22
d. Imaging experiments for aggregation studies...................................................22
3.4.2. Preliminary observations from the cell model.............................................22
a. Transfection of 84Q-eGFP into HEK293T..............................................................22
3.5. Review of literature: Animal models....................................................................24
3.6. Rationale behind our choice of animal model................................................25
3.7. Objectives......................................................................................................................25
3.8. Animal model studies: MJD 84.2 mice...............................................................27
3.8.1. Experimental setup to confirm the functionality of the animal model ...................................................................................................................................................27
a. Animals............................................................................................................................. 27
b. Rotarod.............................................................................................................................28
c. Footprint pattern analysis......................................................................................... 28
d. Locomotor activity...................................................................................................... 29
3.8.2. Preliminary observations from the animal model – MJD 84.2.............30
a. External morphological differences......................................................................30
b. Rotarod............................................................................................................................31
c. Foot print analysis........................................................................................................31
d. Activity through locomotion...................................................................................32
4. Summary.....................................................................................................................33
Chapter 2: Identification of potential drugs for treatment of spinocerebellar ataxia type 3…………………………………………………………………………………………….36
1. Introduction to previously identified treatment strategies.........................36
1.1. Review of literature: Evidence based on previously published articles36
1.1.1. Reducing the levels of expanded protein....................................................36
1.1.2. Preventing the oligomerization and aggregation....................................37
1.1.3. Activating clearance mechanisms...................................................................38
1.1.4. Neuroprotection and other indirect ways....................................................39
a. Use of stem cells and neurotropic factors........................................................39
b. Use of various drugs to alleviate the symptoms............................................40
2. Introduction to our drug of interest – n-butylidenephthalide..................42
3. Preliminary evidence: The effect of n-BP on SCA3 cell model...................42
3.1. Objectives.......................................................................................................................42
3.2. Evidence from cell model..........................................................................................42
3.2.1. Materials and Methods..........................................................................................42
a. Chemicals........................................................................................................................42
3.2.2. Results..........................................................................................................................42
4. Preliminary evidence: The effect of n-BP on SCA3 animal model............43
4.1. Objectives......................................................................................................................45
4.2. Evidence from animal model.................................................................................46
4.2.1. Methods.................................................................................................................46
4.2.2. Results.....................................................................................................................46
a. n-BP induced mitigation of motor impairment observed through recovered motor coordination in SCA3 mice...........................................................................46
b. Decreased locomotor activity was restored after n-BP treatment in SCA3 mice.....................................................................................................................................47
c. Gait analysis reflects similar positive effects by n-BP on SCA3 mice....49
5. Summary...................................................................................................................50
Chapter 3: Mechanisms behind the decrease in ATXN3 by n-BP...............54
1. Introduction: Previously identified target pathways...................................54
1.1. Target pathways affected in SCA3..................................................................54
1.1.1. Chaperones..........................................................................................................54
1.1.2. Ubiquitin – proteasome pathway................................................................55
1.1.3. Autophagy............................................................................................................56
1.1.4. Mitochondrial dysfunction.............................................................................57
1.1.5. Proteolytic mechanisms...................................................................................58
a. Toxic fragment hypothesis.................................................................................58

2. Observation of change in various markers in SCA3 disease post treatment with n-BP...........................................................................................................................60

2.1. Objectives................................................................................................................60
2.2. Materials and Methods......................................................................................61
a. Protein isolation and Western blot....................................................................61
b. Immunohistochemistry..........................................................................................62
c. Cresyl violet staining................................................................................................62
d. RNA isolation and microarray..............................................................................63
e. Quantitative RT-PCR................................................................................................63
2.3. Results ......................................................................................................................63
2.3.1. Pro-proliferation and anti-aggregating capacities of n-BP mitigates improvement in SCA3 neuropathology................................................................63
2.3.2. Tryptophan metabolism through TDO2 contributes to increased neurodegenrative pathology in SCA3....................................................................66
2.4. Observations............................................................................................................70
3. Summary.......................................................................................................................70
Chapter 4: Pathways elaborated...............................................................................74
1. Introduction of the identified pathways of interest......................................74
2. Identification of association between the two pathways...........................76
2.1. Objectives..................................................................................................................76
2.2. Materials and Methods........................................................................................77
a. Isogenic HEK 293T cell lines for 84Q-eGFP and TDO2 expression.........77
b. Chemicals.....................................................................................................................77
c. Quinolinic acid injection cerebellar injection in SCA3 mice......................77
2.3. Results……………………………………………………………………………………............80
2.3.1. As a downstream toxic endproduct of TDO2, QA can deteriorate behavior in SCA3 mice …………………………………………………................................80
2.3.2. Calcium-dependent calpain is also upregulated in SCA3 mice and cell models. ………………………………………………….................................………………........81
2.3.3. Toxic fragment formation is associated with TDO2 expression......83
2.3.4. Ryanodine receptor inhibition does not decrease toxic fragment formation in the SCA3 cell model..............................………………........................85
3. Summary..............................……………….......................…….................................85
Chapter 5: Conclusion and Future.........................................................................88
1. Conclusion..............................................................................................................88
2. Contribution by this study...................................................................................93
3. Future of this study.................................................................................................94
References......................................................................................................................95

Adachi, N., Arima, K., Asada, T., Kato, M., Minami, N., Goto, Y., Onuma, T., Ikeuchi, T., Tsuji, S., Hayashi, M., Fukutani, Y., 2001. Dentatorubral-pallidoluysian atrophy (DRPLA) presenting with psychosis. J Neuropsychiatry Clin Neurosci 13, 258-260.
Al-Ramahi, I., Lam, Y. C., Chen, H. K., de Gouyon, B., Zhang, M., Perez, A. M., Branco, J., de Haro, M., Patterson, C., Zoghbi, H. Y., Botas, J., 2006. CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem 281, 26714-26724.
Alonso, E., Martinez-Ruano, L., De Biase, I., Mader, C., Ochoa, A., Yescas, P., Gutierrez, R., White, M., Ruano, L., Fragoso-Benitez, M., Ashizawa, T., Bidichandani, S. I., Rasmussen, A., 2007. Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population. Mov Disord 22, 1050-1053.
Alonso, M. E., Ochoa, A., Boll, M. C., Sosa, A. L., Yescas, P., Lopez, M., Macias, R., Familiar, I., Rasmussen, A., 2009. Clinical and genetic characteristics of Mexican Huntington's disease patients. Mov Disord 24, 2012-2015.
Alves, S., Cormier-Dequaire, F., Marinello, M., Marais, T., Muriel, M. P., Beaumatin, F., Charbonnier-Beaupel, F., Tahiri, K., Seilhean, D., El Hachimi, K., Ruberg, M., Stevanin, G., Barkats, M., den Dunnen, W., Priault, M., Brice, A., Durr, A., Corvol, J. C., Sittler, A., 2014. The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice. Acta Neuropathol 128, 705-722.
Aziz, N. A., van der Burg, J. M., Landwehrmeyer, G. B., Brundin, P., Stijnen, T., Roos, R. A., 2008. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 71, 1506-1513.
Bates, G., 2003. Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361, 1642-1644.
Berridge, M. J., 1998. Neuronal calcium signaling. Neuron 21, 13-26.
Bettencourt, C., Santos, C., Montiel, R., Costa Mdo, C., Cruz-Morales, P., Santos, L. R., Simoes, N., Kay, T., Vasconcelos, J., Maciel, P., Lima, M., 2010. Increased transcript diversity: novel splicing variants of Machado-Joseph disease gene (ATXN3). Neurogenetics 11, 193-202.
Bichelmeier, U., Schmidt, T., Hubener, J., Boy, J., Ruttiger, L., Habig, K., Poths, S., Bonin, M., Knipper, M., Schmidt, W. J., 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.
Blount, J. R., Tsou, W. L., Ristic, G., Burr, A. A., Ouyang, M., Galante, H., Scaglione, K. M., Todi, S. V., 2014. Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun 5, 4638.
Boy, J., Schmidt, T., Schumann, U., Grasshoff, U., Unser, S., Holzmann, C., Schmitt, I., Karl, T., Laccone, F., Wolburg, H., Ibrahim, S., Riess, O., 2010. A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats. Neurobiol Dis 37, 284-293.
Boy, J., Schmidt, T., Wolburg, H., Mack, A., Nuber, S., Bottcher, M., Schmitt, I., Holzmann, C., Zimmermann, F., Servadio, A., Riess, O., 2009. Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3. Hum Mol Genet 18, 4282-4295.
Burk, K., Globas, C., Bosch, S., Klockgether, T., Zuhlke, C., Daum, I., Dichgans, J., 2003. Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J Neurol 250, 207-211.
Castilhos, R. M., Souza, A. F., Furtado, G. V., Gheno, T. C., Silva, A. L., Vargas, F. R., Lima, M. A., Barsottini, O., Pedroso, J. L., Godeiro, C., Jr., Salarini, D., Pereira, E. T., Lin, K., Toralles, M. B., Saute, J. A., Rieder, C. R., Quintas, M., Sequeiros, J., Alonso, I., Saraiva-Pereira, M. L., Jardim, L. B., 2014. Huntington disease and Huntington disease-like in a case series from Brazil. Clin Genet 86, 373-377.
Cemal, C. K., Carroll, C. J., Lawrence, L., Lowrie, M. B., Ruddle, P., Al-Mahdawi, S., King, R. H., Pook, M. A., Huxley, C., Chamberlain, S., 2002. YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Hum Mol Genet 11, 1075-1094.
Chang, K. H., Chen, W. L., Lee, L. C., Lin, C. H., Kung, P. J., Lin, T. H., Wu, Y. C., Wu, Y. R., Chen, Y. C., Lee-Chen, G. J., Chen, C. M., 2013. Aqueous Extract of Paeonia lactiflora and Paeoniflorin as Aggregation Reducers Targeting Chaperones in Cell Models of Spinocerebellar Ataxia 3. Evid Based Complement Alternat Med 2013, 471659.
Chang, K. H., Chen, W. L., Wu, Y. R., Lin, T. H., Wu, Y. C., Chao, C. Y., Lin, J. Y., Lee, L. C., Chen, Y. C., Lee-Chen, G. J., Chen, C. M., 2014. Aqueous extract of Gardenia jasminoides targeting oxidative stress to reduce polyQ aggregation in cell models of spinocerebellar ataxia 3. Neuropharmacology 81, 166-175.
Chang, W. H., Tien, C. L., Chen, T. J., 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.
Chang, Y. K., Chen, M. H., Chiang, Y. H., Chen, Y. F., Ma, W. H., Tseng, C. Y., Soong, B. W., Ho, J. H., Lee, O. K., 2011. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci 18, 54.
Chen, S., Berthelier, V., Yang, W., Wetzel, R., 2001. Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J Mol Biol 311, 173-182.
Chou, A. H., Yeh, T. H., Ouyang, P., Chen, Y. L., Chen, S. Y., Wang, H. L., 2008. Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis 31, 89-101.
Chuang, H. M., Su, H. L., Li, C., Lin, S. Z., Yen, S. Y., Huang, M. H., Ho, L. I., Chiou, T. W., Harn, H. J., 2016. The Role of Butylidenephthalide in Targeting the Microenvironment Which Contributes to Liver Fibrosis Amelioration. Front Pharmacol 7, 112.
Chung, M. Y., Ranum, L. P., Duvick, L. A., Servadio, A., Zoghbi, H. Y., Orr, H. T., 1993. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat Genet 5, 254-258.
Ciechanover, A., 2006. The ubiquitin proteolytic system: from a vague idea, through basic mechanisms, and onto human diseases and drug targeting. Neurology 66, S7-19.
Colomer Gould, V. F., 2012. Mouse models of spinocerebellar ataxia type 3 (Machado-Joseph disease). Neurotherapeutics 9, 285-296.
Connolly, B. S., Prashanth, L. K., Shah, B. B., Marras, C., Lang, A. E., 2012. A randomized trial of varenicline (chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 79, 2218.
Costa Mdo, C., Paulson, H. L., 2012. Toward understanding Machado-Joseph disease. Prog Neurobiol 97, 239-257.
Cox, H., Costin-Kelly, N. M., Ramani, P., Whitehouse, W. P., 2000. An established case of dentatorubral pallidoluysian atrophy (DRPLA) with unusual features on muscle biopsy. Eur J Paediatr Neurol 4, 119-123.
Cruz-Marino, T., Vazquez-Mojena, Y., Velazquez-Perez, L., Gonzalez-Zaldivar, Y., Aguilera-Rodriguez, R., Velazquez-Santos, M., Estupinan-Rodriguez, A., Laffita-Mesa, J. M., Almaguer-Mederos, L. E., Paneque, M., 2015. SCA2 predictive testing in Cuba: challenging concepts and protocol evolution. J Community Genet 6, 265-273.
Cummings, C. J., Zoghbi, H. Y., 2000. Trinucleotide repeats: mechanisms and pathophysiology. Annu Rev Genomics Hum Genet 1, 281-328.
Davies, J. E., Sarkar, S., Rubinsztein, D. C., 2007. The ubiquitin proteasome system in Huntington's disease and the spinocerebellar ataxias. BMC Biochem 8 Suppl 1, S2.
de Carvalho, L. P., Bochet, P., Rossier, J., 1996. The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits. Neurochem Int 28, 445-452.
Dolusic, E., Larrieu, P., Moineaux, L., Stroobant, V., Pilotte, L., Colau, D., Pochet, L., Van den Eynde, B., Masereel, B., Wouters, J., Frederick, R., 2011. Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators. J Med Chem 54, 5320-5334.
Donaldson, K. M., Li, W., Ching, K. A., Batalov, S., Tsai, C. C., Joazeiro, C. A., 2003. Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc Natl Acad Sci U S A 100, 8892-8897.
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.
Evans, S. J., Douglas, I., Rawlins, M. D., Wexler, N. S., Tabrizi, S. J., Smeeth, L., 2013. Prevalence of adult Huntington's disease in the UK based on diagnoses recorded in general practice records. J Neurol Neurosurg Psychiatry 84, 1156-1160.
Fan, H. C., Ho, L. I., Chi, C. S., Chen, S. J., Peng, G. S., Chan, T. M., Lin, S. Z., Harn, H. J., 2014. Polyglutamine (PolyQ) diseases: genetics to treatments. Cell Transplant 23, 441-458.
Ferrigno, P., Silver, P. A., 2000. Polyglutamine expansions: proteolysis, chaperones, and the dangers of promiscuity. Neuron 26, 9-12.
Fu, R. H., Harn, H. J., Liu, S. P., Chen, C. S., Chang, W. L., Chen, Y. M., Huang, J. E., Li, R. J., Tsai, S. Y., Hung, H. S., Shyu, W. C., Lin, S. Z., Wang, Y. C., 2014. n-butylidenephthalide protects against dopaminergic neuron degeneration and alpha-synuclein accumulation in Caenorhabditis elegans models of Parkinson's disease. PLoS One 9, e85305.
Fujikake, N., Nagai, Y., Popiel, H. A., Okamoto, Y., Yamaguchi, M., Toda, T., 2008. Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones. J Biol Chem 283, 26188-26197.
Gazulla, J., Errea, J. M., Benavente, I., Tordesillas, C. J., 2004. Treatment of ataxia in cortical cerebellar atrophy with the GABAergic drug gabapentin. A preliminary study. Eur Neurol 52, 7-11.
Gehrking, K. M., Andresen, J. M., Duvick, L., Lough, J., Zoghbi, H. Y., Orr, H. T., 2011. Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model. Hum Mol Genet 20, 2204-2212.
Giannini, G., Conti, A., Mammarella, S., Scrobogna, M., Sorrentino, V., 1995. The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J Cell Biol 128, 893-904.
Goti, D., Katzen, S. M., Mez, J., Kurtis, N., Kiluk, J., Ben-Haiem, L., Jenkins, N. A., Copeland, N. G., Kakizuka, A., Sharp, A. H., Ross, C. A., Mouton, P. R., 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.
Graham, F. L., Smiley, J., Russell, W. C., Nairn, R., 1977. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol 36, 59-74.
Green, E. W., Campesan, S., Breda, C., Sathyasaikumar, K. V., Muchowski, P. J., Schwarcz, R., Kyriacou, C. P., Giorgini, F., 2012. Drosophila eye color mutants as therapeutic tools for Huntington disease. Fly (Austin) 6, 117-120.
Haacke, A., Broadley, S. A., Boteva, R., Tzvetkov, N., Hartl, F. U., 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.
Haacke, A., Hartl, F. U., Breuer, P., 2007. Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem 282, 18851-18856.
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., Mizushima, N., 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889.
Hilliard, F. A., Steele, D. S., Laver, D., Yang, Z., Le Marchand, S. J., Chopra, N., Piston, D. W., Huke, S., Knollmann, B. C., 2010. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J Mol Cell Cardiol 48, 293-301.
Holmberg, M., Duyckaerts, C., Dürr, A., Cancel, G., Gourfinkel-An, I., Damier, P., Faucheux, B., Trottier, Y., Hirsch, E. C., Agid, Y., Brice, A., 1998. Spinocerebellar Ataxia Type 7 (SCA7): A Neurodegenerative Disorder With Neuronal Intranuclear Inclusions. Human Molecular Genetics 7, 913-918.
Hu, J., Matsui, M., Gagnon, K. T., Schwartz, J. C., Gabillet, S., Arar, K., Wu, J., Bezprozvanny, I., Corey, D. R., 2009. Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat Biotechnol 27, 478-484.
Hubener, J., Weber, J. J., Richter, C., Honold, L., Weiss, A., Murad, F., Breuer, P., Wullner, U., Bellstedt, P., Paquet-Durand, F., Takano, J., Saido, T. C., Riess, O., Nguyen, H. P., 2013. Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Hum Mol Genet 22, 508-518.
Ikeda, H., Yamaguchi, M., Sugai, S., Aze, Y., Narumiya, S., Kakizuka, A., 1996. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13, 196-202.
Ishida, Y., Kawakami, H., Kitajima, H., Nishiyama, A., Sasai, Y., Inoue, H., Muguruma, K., 2016. Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs. Cell Rep 17, 1482-1490.
Ishiguro, T., Ishikawa, K., Takahashi, M., Obayashi, M., Amino, T., Sato, N., Sakamoto, M., Fujigasaki, H., Tsuruta, F., Dolmetsch, R., Arai, T., Sasaki, H., Nagashima, K., Kato, T., Yamada, M., Takahashi, H., Hashizume, Y., Mizusawa, H., 2010. The carboxy-terminal fragment of alpha(1A) calcium channel preferentially aggregates in the cytoplasm of human spinocerebellar ataxia type 6 Purkinje cells. Acta Neuropathol 119, 447-464.
Jana, N. R., Nukina, N., 2004. Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJD. Neurotox Res 6, 523-533.
Jardim, L. B., Silveira, I., Pereira, M. L., 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.
Jiang, H., Tang, B. S., Xu, B., Zhao, G. H., Shen, L., Tang, J. G., Li, Q. H., Xia, K., 2005. Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Chin Med J (Engl) 118, 837-843.
Jonasson, J., Juvonen, V., Sistonen, P., Ignatius, J., Johansson, D., Bjorck, E. J., Wahlstrom, J., Melberg, A., Holmgren, G., Forsgren, L., Holmberg, M., 2000. Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia. Eur J Hum Genet 8, 918-922.
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.
Kawai, Y., Takeda, A., Abe, Y., Washimi, Y., Tanaka, F., Sobue, G., 2004. Cognitive impairments in Machado-Joseph disease. Arch Neurol 61, 1757-1760.
Kiehl, T. R., Nechiporuk, A., Figueroa, K. P., Keating, M. T., Huynh, D. P., Pulst, S. M., 2006. Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochem Biophys Res Commun 339, 17-24.
Kish, S. J., el-Awar, M., Stuss, D., Nobrega, J., Currier, R., Aita, J. F., Schut, L., Zoghbi, H. Y., Freedman, M., 1994. Neuropsychological test performance in patients with dominantly inherited spinocerebellar ataxia: relationship to ataxia severity. Neurology 44, 1738-1746.
Klionsky, D. J., Emr, S. D., 2000. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721.
Klockgether, T., Ludtke, R., Kramer, B., Abele, M., Burk, K., Schols, L., Riess, O., Laccone, F., Boesch, S., Lopes-Cendes, I., Brice, A., Inzelberg, R., Zilber, N., Dichgans, J., 1998. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 121 ( Pt 4), 589-600.
Knippenberg, S., Thau, N., Dengler, R., Petri, S., 2010. Significance of behavioural tests in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Behav Brain Res 213, 82-87.
Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tuting, T., Hoffmann, P., Klockgether, T., Evert, B. O., Wullner, U., Brustle, O., 2011. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480, 543-546.
Koide, R., Onodera, O., Ikeuchi, T., Kondo, R., Tanaka, H., Tokiguchi, S., Tomoda, A., Miike, T., Isa, F., Beppu, H., Shimizu, N., Watanabe, Y., Horikawa, Y., Shimohata, T., Hirota, K., Ishikawa, A., Tsuji, S., 1997. Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy. Influence of CAG repeat size on MRI findings. Neurology 49, 1605-1612.
Kordasiewicz, H. B., Gomez, C. M., 2007. Molecular pathogenesis of spinocerebellar ataxia type 6. Neurotherapeutics 4, 285-294.
Kraft, S., Furtado, S., Ranawaya, R., Parboosingh, J., Bleoo, S., McElligott, K., Bridge, P., Spacey, S., Das, S., Suchowersky, O., 2005. Adult onset spinocerebellar ataxia in a Canadian movement disorders clinic. Can J Neurol Sci 32, 450-458.
La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E., Fischbeck, K. H., 1991. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77-79.
Laco, M. N., Oliveira, C. R., Paulson, H. L., Rego, A. C., 2012. Compromised mitochondrial complex II in models of Machado-Joseph disease. Biochim Biophys Acta 1822, 139-149.
Lei, L. F., Yang, G. P., Wang, J. L., Chuang, D. M., Song, W. H., Tang, B. S., Jiang, H., 2016. Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord 26, 55-61.
Lerer, I., Merims, D., Abeliovich, D., Zlotogora, J., Gadoth, N., 1996. Machado-Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur J Hum Genet 4, 3-7.
Lima, L., Coutinho, P., 1980. Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azorena Portuguese family. Neurology 30, 319-322.
Lin, A. H., Sun, H., Paudel, O., Lin, M. J., Sham, J. S., 2016. Conformation of ryanodine receptor-2 gates store-operated calcium entry in rat pulmonary arterial myocytes. Cardiovasc Res 111, 94-104.
Lin, X. P., Feng, L., Xie, C. G., Chen, D. B., Pei, Z., Liang, X. L., Xie, Q. Y., Li, X. H., Pan, S. Y., 2014. Valproic acid attenuates the suppression of acetyl histone H3 and CREB activity in an inducible cell model of Machado-Joseph disease. Int J Dev Neurosci 38, 17-22.
Liu, C. S., Hsu, H. M., Cheng, W. L., Hsieh, M., 2005. Clinical and molecular events in patients with Machado-Joseph disease under lamotrigine therapy. Acta Neurol Scand 111, 385-390.
Magazi, D. S., Krause, A., Bonev, V., Moagi, M., Iqbal, Z., Dludla, M., van der Meyden, C. H., 2008. Huntington's disease: genetic heterogeneity in black African patients. S Afr Med J 98, 200-203.
Manto, M. U., 2005. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 4, 2-6.
Margulis, B. A., Vigont, V., Lazarev, V. F., Kaznacheyeva, E. V., Guzhova, I. V., 2013. Pharmacological protein targets in polyglutamine diseases: Mutant polypeptides and their interactors. FEBS Letters 587, 1997-2007.
Marsh, J. L., Walker, H., Theisen, H., Zhu, Y. Z., Fielder, T., Purcell, J., Thompson, L. M., 2000. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum Mol Genet 9, 13-25.
Maruff, P., Tyler, P., Burt, T., Currie, B., Burns, C., Currie, J., 1996. Cognitive deficits in Machado-Joseph disease. Ann Neurol 40, 421-427.
Maruyama, H., Izumi, Y., Morino, H., Oda, M., Toji, H., Nakamura, S., Kawakami, H., 2002. Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients. Am J Med Genet 114, 578-583.
Mascalchi, M., Toschi, N., Giannelli, M., Ginestroni, A., Della Nave, R., Nicolai, E., Bianchi, A., Tessa, C., Salvatore, E., Aiello, M., Soricelli, A., Diciotti, S., 2015. Progression of Microstructural Damage in Spinocerebellar Ataxia Type 2: A Longitudinal DTI Study. American Journal of Neuroradiology 36, 1096-1101.
Matilla-Duenas, A., 2012. Machado-Joseph disease and other rare spinocerebellar ataxias. Adv Exp Med Biol 724, 172-188.
Matilla, A., Roberson, E. D., Banfi, S., Morales, J., Armstrong, D. L., Burright, E. N., Orr, H. T., Sweatt, J. D., Zoghbi, H. Y., Matzuk, M. M., 1998. Mice lacking ataxin-1 display learning deficits and decreased hippocampal paired-pulse facilitation. J Neurosci 18, 5508-5516.
Matos, C. A., de Macedo-Ribeiro, S., Carvalho, A. L., 2011. Polyglutamine diseases: the special case of ataxin-3 and Machado-Joseph disease. Prog Neurobiol 95, 26-48.
Maura, G., Raiteri, M., 1996. Serotonin 5-HT1D and 5-HT1A receptors respectively mediate inhibition of glutamate release and inhibition of cyclic GMP production in rat cerebellum in vitro. J Neurochem 66, 203-209.
Mendonca, L. S., Nobrega, C., Hirai, H., Kaspar, B. K., Pereira de Almeida, L., 2015. Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice. Brain 138, 320-335.
Menzies, F. M., Huebener, J., Renna, M., Bonin, M., Riess, O., Rubinsztein, D. C., 2010. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133, 93-104.
Michalik, A., Martin, J. J., Van Broeckhoven, C., 2004. Spinocerebellar ataxia type 7 associated with pigmentary retinal dystrophy. Eur J Hum Genet 12, 2-15.
Michalik, A., Van Broeckhoven, C., 2003. Pathogenesis of polyglutamine disorders: aggregation revisited. Human Molecular Genetics 12, R173-R186.
Miller, V. M., Xia, H., Marrs, G. L., Gouvion, C. M., Lee, G., Davidson, B. L., Paulson, H. L., 2003. Allele-specific silencing of dominant disease genes. Proc Natl Acad Sci U S A 100, 7195-7200.
Monte, T. L., Rieder, C. R., Tort, A. B., Rockenback, I., Pereira, M. L., Silveira, I., Ferro, A., Sequeiros, J., Jardim, L. B., 2003. Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study. Acta Neurol Scand 107, 207-210.
Morrison, P. J., Johnston, W. P., Nevin, N. C., 1995. The epidemiology of Huntington's disease in Northern Ireland. J Med Genet 32, 524-530.
Nagai, Y., Tucker, T., Ren, H., Kenan, D. J., Henderson, B. S., Keene, J. D., Strittmatter, W. J., Burke, J. R., 2000. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem 275, 10437-10442.
Nandagopal, R., Moorthy, S. G., 2004. Dramatic levodopa responsiveness of dystonia in a sporadic case of spinocerebellar ataxia type 3. Postgrad Med J 80, 363-365.
Onodera, Y., Aoki, M., Tsuda, T., Kato, H., Nagata, T., Kameya, T., Abe, K., Itoyama, Y., 2000. High prevalence of spinocerebellar ataxia type 1 (SCA1) in an isolated region of Japan. J Neurol Sci 178, 153-158.
Paulson, H., 2012. Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol 103, 437-449.
Paulson, H. L., Perez, M. K., Trottier, Y., Trojanowski, J. Q., Subramony, S. H., Das, S. S., Vig, P., Mandel, J. L., Fischbeck, K. H., Pittman, R. N., 1997. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19, 333-344.
Pellistri, F., Bucciantini, M., Invernizzi, G., Gatta, E., Penco, A., Frana, A. M., Nosi, D., Relini, A., Regonesi, M. E., Gliozzi, A., Tortora, P., Robello, M., Stefani, M., 2013. Different ataxin-3 amyloid aggregates induce intracellular Ca(2+) deregulation by different mechanisms in cerebellar granule cells. Biochim Biophys Acta 1833, 3155-3165.
Peng, Y., Sun, J., Hon, S., Nylander, A. N., Xia, W., Feng, Y., Wang, X., Lemere, C. A., 2010. L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer's disease. J Neurosci 30, 8180-8189.
Perutz, M. F., Johnson, T., Suzuki, M., Finch, J. T., 1994. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A 91, 5355-5358.
Ratovitski, T., Chighladze, E., Waldron, E., Hirschhorn, R. R., Ross, C. A., 2011. Cysteine proteases bleomycin hydrolase and cathepsin Z mediate N-terminal proteolysis and toxicity of mutant huntingtin. J Biol Chem 286, 12578-12589.
Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., Scaravilli, F., Easton, D. F., Duden, R., O'Kane, C. J., Rubinsztein, D. C., 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.
Reader, T. A., Ase, A. R., Le Marec, N., Lalonde, R., 2000. Differential effects of L-trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum. Neurosci Lett 280, 171-174.
Reader, T. A., Le Marec, N., Ase, A. R., Lalonde, R., 1999. Effects of L-tryptophan on indoleamines and catecholamines in discrete brain regions of wild type and Lurcher mutant mice. Neurochem Res 24, 1125-1134.
Rengaraj, R., Dhanaraj, M., Arulmozhi, T., Chattopadhyay, B., Battacharyya, N. P., 2005. High prevalence of spinocerebellar ataxia type 1 in an ethnic Tamil community in India. Neurol India 53, 308-310; discussion 311.
Riley, B. E., Orr, H. T., 2006. Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes Dev 20, 2183-2192.
Salter, M., Hazelwood, R., Pogson, C. I., Iyer, R., Madge, D. J., 1995. The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat. Biochem Pharmacol 49, 1435-1442.
Salter, M., Hazelwood, R., Pogson, C. I., Iyer, R., Madge, D. J., Jones, H. T., Cooper, B. R., Cox, R. F., Wang, C. M., Wiard, R. P., 1996. The effects of a selective inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake on serotonergic function in the rat. Adv Exp Med Biol 398, 61-65.
Schmidt, J., Schmidt, T., Golla, M., Lehmann, L., Weber, J. J., Hubener-Schmid, J., Riess, O., 2016. In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3. J Neurochem 138, 150-162.
Schneider, S. A., Walker, R. H., Bhatia, K. P., 2007. The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test. Nat Clin Pract Neurol 3, 517-525.
Schols, L., Amoiridis, G., Buttner, T., Przuntek, H., Epplen, J. T., Riess, O., 1997. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 42, 924-932.
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.
Schulte, J., Littleton, J. T., 2011. The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology. Curr Trends Neurol 5, 65-78.
Shao, J., Diamond, M. I., 2007. Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet 16 Spec No. 2, R115-123.
Shaw, G., Morse, S., Ararat, M., Graham, F. L., 2002. Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells. Faseb j 16, 869-871.
Shibata-Hamaguchi, A., Ishida, C., Iwasa, K., Yamada, M., 2009. Prevalence of spinocerebellar degenerations in the Hokuriku district in Japan. Neuroepidemiology 32, 176-183.
Shiotsuki, H., Yoshimi, K., Shimo, Y., Funayama, M., Takamatsu, Y., Ikeda, K., Takahashi, R., Kitazawa, S., Hattori, N., 2010. A rotarod test for evaluation of motor skill learning. J Neurosci Methods 189, 180-185.
Silva-Fernandes, A., Costa Mdo, C., Duarte-Silva, S., Oliveira, P., Botelho, C. M., Martins, L., Mariz, J. A., Ferreira, T., Ribeiro, F., Correia-Neves, M., Costa, C., Maciel, P., 2010. Motor uncoordination and neuropathology in a transgenic mouse model of Machado-Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products. Neurobiol Dis 40, 163-176.
Silveira, I., Coutinho, P., Maciel, P., Gaspar, C., Hayes, S., Dias, A., Guimaraes, J., Loureiro, L., Sequeiros, J., Rouleau, G. A., 1998. Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families. Am J Med Genet 81, 134-138.
Simoes, A. T., Goncalves, N., Koeppen, A., Deglon, N., Kugler, S., Duarte, C. B., Pereira de Almeida, L., 2012. Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. Brain 135, 2428-2439.
Sinha, K. K., Worth, P. F., Jha, D. K., Sinha, S., Stinton, V. J., Davis, M. B., Wood, N. W., Sweeney, M. G., Bhatia, K. P., 2004. Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India. J Neurol Neurosurg Psychiatry 75, 448-452.
Smith, D. C., Bryer, A., Watson, L. M., Greenberg, L. J., 2012. Inherited polyglutamine spinocerebellar ataxias in South Africa. S Afr Med J 102, 683-686.
Soong, B. W., Lu, Y. C., Choo, K. B., Lee, H. Y., 2001. Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Arch Neurol 58, 1105-1109.
Soong, B. W., Paulson, H. L., 2007. Spinocerebellar ataxias: an update. Curr Opin Neurol 20, 438-446.
Stevanin, G., Brice, A., 2008. Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4). Cerebellum 7, 170-178.
Stevanin, G., Herman, A., Brice, A., Durr, A., 1999. Clinical and MRI findings in spinocerebellar ataxia type 5. Neurology 53, 1355-1357.
Stone, T. W., Darlington, L. G., 2013. The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol 169, 1211-1227.
Storey, E., du Sart, D., Shaw, J. H., Lorentzos, P., Kelly, L., McKinley Gardner, R. J., Forrest, S. M., Biros, I., Nicholson, G. A., 2000. Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia. Am J Med Genet 95, 351-357.
Takiyama, Y., Oyanagi, S., Kawashima, S., Sakamoto, H., Saito, K., Yoshida, M., Tsuji, S., Mizuno, Y., Nishizawa, M., 1994. A clinical and pathologic study of a large Japanese family with Machado-Joseph disease tightly linked to the DNA markers on chromosome 14q. Neurology 44, 1302-1308.
Tan, S., Wang, R. H., Niu, H. X., Shi, C. H., Mao, C. Y., Zhang, R., Song, B., Sun, S. L., Liu, X. J., Hou, H. M., Liu, Y. T., Gao, Y., Fang, H., Kong, X. D., Xu, Y. M., 2015. Nerve growth factor for the treatment of spinocerebellar ataxia type 3: an open-label study. Chin Med J (Engl) 128, 291-294.
Tang, B., Liu, C., Shen, L., Dai, H., Pan, Q., Jing, L., Ouyang, S., Xia, J., 2000. Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol 57, 540-544.
Teive, H. A., 2009. Spinocerebellar ataxias. Arq Neuropsiquiatr 67, 1133-1142.
Teive, H. A., Munhoz, R. P., Raskin, S., Werneck, L. C., 2008. Spinocerebellar ataxia type 6 in Brazil. Arq Neuropsiquiatr 66, 691-694.
Trottier, Y., Cancel, G., An-Gourfinkel, I., Lutz, Y., Weber, C., Brice, A., Hirsch, E., Mandel, J. L., 1998. Heterogeneous intracellular localization and expression of ataxin-3. Neurobiol Dis 5, 335-347.
Trouillas, P., Xie, J., Adeleine, P., Michel, D., Vighetto, A., Honnorat, J., Dumas, R., Nighoghossian, N., Laurent, B., 1997. Buspirone, a 5-hydroxytryptamine1A agonist, is active in cerebellar ataxia. Results of a double-blind drug placebo study in patients with cerebellar cortical atrophy. Arch Neurol 54, 749-752.
Tsai, H. F., Liu, C. S., Leu, T. M., Wen, F. C., Lin, S. J., Liu, C. C., Yang, D. K., Li, C., Hsieh, M., 2004. Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan. Acta Neurol Scand 109, 355-360.
Tsai, N. M., Chen, Y. L., Lee, C. C., Lin, P. C., Cheng, Y. L., Chang, W. L., Lin, S. Z., Harn, H. J., 2006. The natural compound n-butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo. J Neurochem 99, 1251-1262.
Tsuji, S., 2012. Dentatorubral-pallidoluysian atrophy. Handb Clin Neurol 103, 587-594.
Vale, J., Bugalho, P., Silveira, I., Sequeiros, J., Guimaraes, J., Coutinho, P., 2010. Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal. Eur J Neurol 17, 124-128.
van de Warrenburg, B. P., Sinke, R. J., Verschuuren-Bemelmans, C. C., Scheffer, H., Brunt, E. R., Ippel, P. F., Maat-Kievit, J. A., Dooijes, D., Notermans, N. C., Lindhout, D., Knoers, N. V., Kremer, H. P., 2002. Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology 58, 702-708.
Verkhratsky, A., 2005. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev 85, 201-279.
Villani, F., Gellera, C., Spreafico, R., Castellotti, B., Casazza, M., Carrara, F., Avanzini, G., 1998. Clinical and molecular findings in the first identified Italian family with dentatorubral-pallidoluysian atrophy. Acta Neurol Scand 98, 324-327.
Walker, F. O., 2007. Huntington's disease. Lancet 369, 218-228.
Warner, T. T., Williams, L. D., Walker, R. W., Flinter, F., Robb, S. A., Bundey, S. E., Honavar, M., Harding, A. E., 1995. A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families. Ann Neurol 37, 452-459.
Warrick, J. M., Chan, H. Y., Gray-Board, G. L., Chai, Y., Paulson, H. L., Bonini, N. M., 1999. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23, 425-428.
Weber, J. J., Sowa, A. S., Binder, T., Hubener, J., 2014. From pathways to targets: understanding the mechanisms behind polyglutamine disease. Biomed Res Int 2014, 701758.
Winborn, B. J., Travis, S. M., Todi, S. V., Scaglione, K. M., Xu, P., Williams, A. J., Cohen, R. E., Peng, J., Paulson, H. L., 2008. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283, 26436-26443.
Xiang, J., Pan, J., Chen, F., Zheng, L., Chen, Y., Zhang, S., Feng, W., 2014. L-3-n-butylphthalide improves cognitive impairment of APP/PS1 mice by BDNF/TrkB/PI3K/AKT pathway. Int J Clin Exp Med 7, 1706-1713.
Xiong, N., Huang, J., Chen, C., Zhao, Y., Zhang, Z., Jia, M., Zhang, Z., Hou, L., Yang, H., Cao, X., Liang, Z., Zhang, Y., Sun, S., Lin, Z., Wang, T., 2012. Dl-3-n-butylphthalide, a natural antioxidant, protects dopamine neurons in rotenone models for Parkinson's disease. Neurobiol Aging 33, 1777-1791.
Xu, J., Wang, Y., Li, N., Xu, L., Yang, H., Yang, Z., 2012. L-3-n-butylphthalide improves cognitive deficits in rats with chronic cerebral ischemia. Neuropharmacology 62, 2424-2429.
Yabe, I., Sasaki, H., Yamashita, I., Takei, A., Tashiro, K., 2001. Clinical trial of acetazolamide in SCA6, with assessment using the Ataxia Rating Scale and body stabilometry. Acta Neurol Scand 104, 44-47.
Yamamoto, A., Lucas, J. J., Hen, R., 2000. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57-66.
Yorimitsu, T., Klionsky, D. J., 2005. Autophagy: molecular machinery for self-eating. Cell Death Differ 12 Suppl 2, 1542-1552.
Zawacki, T. M., Grace, J., Friedman, J. H., Sudarsky, L., 2002. Executive and emotional dysfunction in Machado-Joseph disease. Mov Disord 17, 1004-1010.
Zesiewicz, T. A., Greenstein, P. E., Sullivan, K. L., Wecker, L., Miller, A., Jahan, I., Chen, R., Perlman, S. L., 2012. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 78, 545-550.
Zhang, L., Yu, W. H., Wang, Y. X., Wang, C., Zhao, F., Qi, W., Chan, W. M., Huang, Y., Wai, M. S., Dong, J., Yew, D. T., 2012. DL-3-n-Butylphthalide, an anti-oxidant agent, prevents neurological deficits and cerebral injury following stroke per functional analysis, magnetic resonance imaging and histological assessment. Curr Neurovasc Res 9, 167-175.
Zhao, Y., Tan, E. K., Law, H. Y., Yoon, C. S., Wong, M. C., Ng, I., 2002. Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore. Clin Genet 62, 478-481.
Zoghbi, H. Y., Orr, H. T., 2000. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23, 217-247.
Zortea, M., Armani, M., Pastorello, E., Nunez, G. F., Lombardi, S., Tonello, S., Rigoni, M. T., Zuliani, L., Mostacciuolo, M. L., Gellera, C., Di Donato, S., Trevisan, C. P., 2004. Prevalence of inherited ataxias in the province of Padua, Italy. Neuroepidemiology 23, 275-280.