Abstract
CAG repeat diseases are hereditary neurodegenerative disorders caused by expansion of a polyglutamine tract in each respective disease protein. They include at least nine disorders, including Huntington’s disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and the spinocerebellar ataxias SCA1, SCA2, SCA3 (also known as Machado-Joseph disease), SCA6, SCA7, and SCA17. It is thought that a gain of toxic function resulting from the protein mutation plays important and common roles in the pathogenesis of these diseases. Recent studies have disclosed that, in addition to the presence of clinical phenotypes and conventional neuropathology in each disease, human brains affected by CAG repeat diseases share several polyglutamine-related changes in their neuronal nuclei and cytoplasm including the formation of intranuclear inclusions. Although these novel pathologic changes also show a distribution pattern characteristic to each disease, they are generally present beyond the lesion distribution of neuronal loss, suggesting that neurons are affected much more widely than has been recognized previously. Various mouse models of CAG repeat diseases have revealed that CAG repeat lengths, which are responsible for polyglutamine diseases in humans, are not sufficient for creating the conditions characteristic of each disease in mice. Although high expression of mutant proteins in mice results in the successful generation of polyglutamine-related changes in the brain, there are still some differences from human pathology in the lesion distribution or cell types that are affected. In addition, no model has yet successfully reproduced the specific neuronal loss observed in humans. Although there are no models that fully represent the neuropathologic changes present in humans, the data obtained have provided evidence that clinical onset is not clearly associated with neuronal cell death, but depends on intranuclear accumulation of mutant proteins in neurons.
Similar content being viewed by others
References
Abel A, Walcott J, Woods J, Duda J, Merry DE (2001) Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 10:107–116
Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Do J, Sang C, Kobayashi Y, Doyu M, Sobue G (2001) Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death. Hum Mol Genet 10:1039–1048
Aguiar J, Fernández J, Aguilar A, Mendoza Y, Vázquez M, Suárez J, Berlanga J, Cruz S, Guillén G, Herrera L, Velázquez L, Santos N, Merino N (2006) Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specific Purkinje cell degeneration in transgenic mice. Neurosci Lett 392:202–206
Bichelmeier U, Schmidt T, Hübener J, Boy J, Rüttiger L, Häbig 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
Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HT (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82:937–948
Carpenter S, Schumacher GA (1966) Familial infantile cerebellar atrophy associated with retinal degeneration. Arch Neurol 14:82–94
Cemal CK, Carroll CJ, Lawrence L, Lowrie MB, Ruddle P, Al-Mahdawi S, King RHM, Pook MA, 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
Clark HB, Burright EN, Yunis WS, Larson S, Wilcox C, Hartman B, Matilla A, Zoghbi HY, Orr HT (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
Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y, Ciechanover A, Orr HT, Beaudet AL, Zoghbi HY (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24:879–892
Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548
Day JW, Schut LJ, Moseley ML, Durand AC, Ranum LP (2000) Spinocerebellar ataxia type 8: clinical features in a large family. Neurology 55:649–657
de Jong PT, de Jong JG, de Jong-Ten Doeschate JM, Delleman JW (1980) Olivopontocerebellar atrophy with visual disturbances. An ophthalmologic investigation into four generations. Ophthalmology 87:793–804
del Toro D, Canals JM, Gines S, Kojima M, Egea G, Alberch J (2006) Mutant huntingtin impairs the post-Golgi trafficking of brain-derived neurotrophic factor but not its Val66Met polymorphism. J Neurosci 26:12748–12757
Dürr A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J, Bellance R, Buisson GG, Chneiweiss H, Dellanave J, Agid Y, Brice A, Vernant JC (1995) Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 118 (Pt 6):1573–1581
Duyckaerts C, Dürr A, Cancel G, Brice A (1999) Nuclear inclusions in spinocerebellar ataxia type 1. Acta Neuropathol 97:201–207
Enevoldson TP, Sanders MD, Harding AE (1994) Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families. Brain 117:445–460
Everett CM, Wood NW (2004) Trinucleotide repeats and neurodegenerative disease. Brain 127:2385–2405
Fan MM, Fernandes HB, Zhang LY, Hayden MR, Raymond LA (2007) Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington’s disease. J Neurosci 27:3768–3779
Garden GA, Libby RT, Fu YH, Kinoshita Y, Huang J, Possin DE, Smith AC, Martinez RA, Fine GC, Grote SK, Ware CB, Einum DD, Morrison RS, Ptacek LJ, Sopher BL, La Spada AR (2002) Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J Neurosci 22:4897–4905
Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, Ben-Haïm 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
Gouw LG, Digre KB, Harris CP, Haines JH, Ptacek LJ (1994) Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 44:1441–1447
Gouw LG, Kaplan CD, Haines JH, Digre KB, Rutledge SL, Matilla A, Leppert M, Zoghbi HY, Ptacek LJ (1995) Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet 10:89–93
Harding AE, Thomas PK, Baraitser M, Bradbury PG, Morgan-Hughes JA, Ponsford JR (1982) X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry 45:1012–1019
Hayashi Y, Kakita A, Yamada M, Koide R, Igarashi S, Takano H, Ikeuchi T, Wakabayashi K, Egawa S, Tsuji S, Takahashi H (1998) Hereditary dentatorubral-pallidoluysian atrophy: detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain. Acta Neuropathol 96:547–552
Herbst M, Wanker EE (2006) Therapeutic approaches to polyglutamine diseases: combating protein misfolding and aggregation. Curr Pharm Des 12:2543–2555
Holmberg M, Johansson J, Forsgren L, Heijbel J, Sandgren O, Holmgren G (1995) Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1. Hum Mol Genet 4:1441–1445
Holmberg M, Duyckaerts C, Dürr A, Cancel G, Gourfinkel-An I, Damier P, Faucheux B, Trottier Y, Hirsch EC, Agid Y, Brice A (1998) Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 7:913–918
Huynh DP, Del Bigio MR, Ho DH, Pulst SM (1999) Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol 45:232–241
Huynh DP, Figueroa K, Hoang N, Pulst SM (2000) Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet 26:44–50
Ikeda Y, Shizuka M, Watanabe M, Okamoto K, Shoji M (2000) Molecular and clinical analyses of spinocerebellar ataxia type 8 in Japan. Neurology 54:950–955
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
Ikeuchi T, Takano H, Koide R, Horikawa Y, Honma Y, Onishi Y, Igarashi S, Tanaka H, Nakao N, Sahashi K, Tsukagoshi H, Inoue K, Takahashi H, Tsuji S (1997) Spinocerebellar ataxia type 6: CAG repeat expansion in alpha1A voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann Neurol 42:879–884
Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, Dürr A, Didierjean O, Stevanin G, Agid Y, Brice A (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 14:285–291
Ishikawa K, Owada K, Ishida K, Fujigasaki H, Shun Li M, Tsunemi T, Ohkoshi N, Toru S, Mizutani T, Hayashi M, Arai N, Hasegawa K, Kawanami T, Kato T, Makifuchi T, Shoji S, Tanabe T, Mizusawa H (2001) Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells. Neurology 56:1753–1756
Ito H, Kawakami H, Wate R, Matsumoto S, Imai T, Hirano A, Kusaka H (2006) Clinicopathologic investigation of a family with expanded SCA8 CTA/CTG repeats. Neurology 67:1479–1481
Iwabuchi K, Tsuchiya K, Uchihara T, Yagishita S (1999) Autosomal dominant spinocerebellar degenerations. Rev Neurol (Paris) 155:255–270
Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Sang C, Kobayashi Y, Doyu M, Sobue G (2002) Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35:843–854
Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95:41–53
Koide R, Kobayashi S, Shimohata T, Ikeuchi T, Maruyama M, Saito M, Yamada M, Takahashi H, Tsuji S (1999) A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet 8:2047–2053
Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LP (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet 21:379–384
Koyano S, Uchihara T, Fujigasaki H, Nakamura A, Yagishita S, Iwabuchi K (1999) Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study. Neurosci Lett 273:117–120
Koyano S, Iwabuchi K, Yagishita S, Kuroiwa Y, Uchihara T (2002) Paradoxical absence of nuclear inclusion in cerebellar Purkinje cells of hereditary ataxias linked to CAG expansion. J Neurol Neurosurg Psychiatry 73:450–452
La Spada AR, Fu YH, Sopher BL, Libby RT, Wang X, Li LY, Einum DD, Huang J, Possin DE, Smith AC, Martinez RA, Koszdin KL, Treuting PM, Ware CB, Hurley JB, Ptacek LJ, Chen S (2001) Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 31:913–927
Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY (2006) ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127:1335–1347
Li M, Sobue G, Doyu M, Mukai E, Hashizume Y, Mitsuma T (1995) Primary sensory neurons in X-linked recessive bulbospinal neuropathy: histopathology and androgen receptor gene expression. Muscle Nerve 18:301–308
Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G (1998) Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 44:249–254
Li M, Nakagomi Y, Kobayashi Y, Merry DE, Tanaka F, Doyu M, Mitsuma T, Hashizume Y, Fischbeck KH, Sobue G (1998) Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol 153:695–701
Lorenzetti D, Watase K, Xu B, Matzuk MM, Orr HT, Zoghbi HY (2000) Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus. Hum Mol Genet 9:779–785
Luthi-Carter R, Strand AD, Hanson SA, Kooperberg C, Schilling G, La Spada AR, Merry DE, Young AB, Ross CA, Borchelt DR, Olson JM (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington’s disease mouse models reveal context-independent effects. Hum Mol Genet 11:1927–1937
Martin JJ, Van Regemorter N, Krols L, Brucher JM, de Barsy T, Szliwowski H, Evrard P, Ceuterick C, Tassignon MJ, Smet-Dieleman H, Hayez-Delatte F, Willems PJ, Van Broeckhoven C (1994) On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropathol (Berl) 88:277–286
Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, Chen G, Weatherspoon MR, Clark HB, Ebner TJ, Day JW, Ranum LP (2006) Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 38:758–769
Naito H, Oyanagi S (1982) Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral-pallidoluysian atrophy. Neurology 32:798–807
Naito H (1990) The clinical picture and classification of dentatorubral-pallidoluysian atrophy (DRPLA). Shinkeinaika 32:450–456 (in Japanese)
Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, Ikeda S, Tsuji S, Kanazawa I (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10:1441–1448
Neetens A, Martin JJ, Libert J, Van den Ende P (1990) Autosomal dominant cone dystrophy-cerebellar atrophy (ADCoCA) (modified ADCA Harding II). Neuroophthalmology 10:261–275
Ohama E, Shimoda Y, Shimomura T, Katou S, Kimura M (1995) Dentatorubral-pallidoluysian atrophy: a neuropathological study of father and son in a family. Neuropathology 15(suppl):147 (in Japanese)
Orozco G, Estrada R, Perry TL, Araña J, Fernandez R, Gonzalez-Quevedo A, Galarraga J, Hansen S (1989) Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings. J Neurol Sci 93:37–50
Orr HT (2001) Beyond the Qs in the polyglutamine diseases. Gene Dev 15:925–932
Oyanagi K, Aoki K, Morita T, Igarashi S, Inuzuka T, Horikawa Y (1996) Disaggregation of polyribosomes in the spinal anterior horn cells in a patient with X-linked spinal and bulbar muscular atrophy. Acta Neuropathol 91:444–447
Paul S (2007) Polyglutamine-mediated neurodegeneration: use of chaperones as prevention strategy. Biochemistry (Mosc) 72:359–366
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
Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14:269–276
Rosenberg RN (1992) Machado-Joseph disease: an autosomal dominant motor system degeneration. Mov Disord 7:193–203
Ross CA (2002) Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron 35:819–822
Ryan SJ Jr, Knox DL, Green WR, Konigsmark BW (1975) Olivopontocerebellar degeneration. Clinicopathologic correlation of the associated retinopathy. Arch Ophthalmol 93:169–172
Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, Koide R, Saito M, Sato A, Tanaka T, Hanyu S, Takiyama Y, Nishizawa M, Shimizu N, Nomura Y, Segawa M, Iwabuchi K, Eguchi I, Tanaka H, Takahashi H, Tsuji S (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 14:277–284
Sato T, Oyake M, Nakamura K, Nakao K, Fukusima Y, Onodera O, Igarashi S, Takano H, Kikugawa K, Ishida Y, Shimohata T, Koide R, Ikeuchi T, Tanaka H, Futamura N, Matsumura R, Takayanagi T, Tanaka F, Sobue G, Komure O, Takahashi M, Sano A, Ichikawa Y, Goto J, Kanazawa I, Katsuki M, Tsuji S (1999) Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients. Hum Mol Genet 8:99–106
Sato T, Yamada M, Oyake M, Nakao K, Nakamura K, Katsuki M, Takahashi H, Tsuji S (1999) Transgenic mice harboring a full-length human DRPLA gene with highly expanded CAG repeats exhibit severe disease phenotype. Am J Hum Genet 65(suppl):A30
Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66
Schilling G, Wood JD, Duan K, Slunt HH, Gonzales V, Yamada M, Cooper JK, Margolis RL, Jenkins NA, Copeland NG, Takahashi H, Tsuji S, Price DL, Borchelt DR, Ross CA (1999) Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron 24:275–286
Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, Laccone F, Klockgether T, Völpel M, Epplen JT, Schöl L, Riess O (1998) An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 8:669–679
Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S, Kimura T, Koide R, Nozaki K, Sano Y, Ishiguro H, Sakoe K, Ooshima T, Sato A, Ikeuchi T, Oyake M, Sato T, Aoyagi Y, Hozumi I, Nagatsu T, Takiyama Y, Nishizawa M, Goto J, Kanazawa I, Davidson I, Tanese N, Takahashi H, Tsuji S (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26:29–36
Skinner PJ, Koshy BT, Cummings CJ, Klement IA, Helin K, Servadio A, Zoghbi HY, Orr HT (1997) Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389:971–974
Sobue G, Hashizume Y, Mukai E, Hirayama M, Mitsuma T, Takahashi A (1989) X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 112:209–232
Sopher BL, Thomas PS Jr, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM, La Spada AR (2004) Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41:687–699
Sudarsky L, Coutinho P (1995) Machado-Joseph disease. Clin Neurosci 3:17–22
Takahashi H, Egawa S, Piao YS, Hayashi S, Yamada M, Shimohata T, Oyanagi K, Tsuji S (2001) Neuronal nuclear alterations in dentatorubral-pallidoluysian atrophy: ultrastructural and morphometric studies of the cerebellar granule cells. Brain Res 919:12–9
Toyoshima Y, Yamada M, Onodera O, Shimohata M, Inenaga C, Fujita N, Morita M, Tsuji S, Takahashi H (2004) SCA17 homozygote showing Huntington’s disease-like phenotype. Ann Neurol 55:281–286
Traboulsi EI, Maumenee IH, Green WR, Freimer ML, Moser H (1988) Olivopontocerebellar atrophy with retinal degeneration. A clinical and ocular histopathologic study. Arch Ophthalmol 106:801–806
Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L, Agid Y, Brice A, Mandel JL (1995) Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 378:403–406
Truant R, Atwal R, Burtnik A (2006) Hypothesis: Huntingtin may function in membrane association and vesicular trafficking. Biochem Cell Biol 84:912–917
Truant R, Atwal RS, Burtnik A (2007) Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington’s disease. Prog Neurobiol [Epub ahead of print]
Uchihara T, Takeda Y, Kobayashi T, Kasuga T, Ishikawa K, Kirei K, Mizusawa H, Endo T, Hirokawa K, Kuroiwa T (2006) Unexpected clinicopathological phenotype linked to small elongation of CAG repeat in SCA1 gene. J Neurol 253:396–398
Valera AG, Diáz-Hernández M, Hernández F, Lucas JJ (2007) Testing the possible inhibition of proteasome by direct interaction with ubiquitylated and aggregated huntingtin. Brain Res Bull 72:121–123
van de Warrenburg BP, Frenken CW, Ausems MG, Kleefstra T, Sinke RJ, Knoers NV, Kremer HP (2001) Striking anticipation in spinocerebellar ataxia type 7: the infantile phenotype. J Neurol 248:911–914
Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, Hashimoto K, Kano M, Atkinson R, Sun Y, Armstrong DL, Sweatt JD, Orr HT, Paylor R, Zoghbi HY (2002) A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34:905–919
Yamada M, Piao YS, Toyoshima Y, Tsuji S, Takahashi H (2000) Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral-pallidoluysian atrophy contain expanded polyglutamine stretches. Acta Neuropathol (Berl) 99:615–618
Yamada M, Hayashi S, Tsuji S, Takahashi H (2001) Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph disease. Acta Neuropathol (Berl) 101:140–144
Yamada M, Wood JD, Shimohata T, Hayashi S, Tsuji S, Ross CA, Takahashi H (2001) Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy. Ann Neurol 49:14–23
Yamada M, Sato T, Shimohata T, Hayashi S, Igarashi S, Tsuji S, Takahashi H (2001) Interaction between neuronal intranuclear inclusions and promyelocytic leukemia protein nuclear and coiled bodies in CAG repeat diseases. Am J Pathol 159:1785–1795
Yamada M, Tsuji S, Takahashi H (2002) Involvement of lysosomes in the pathogenesis of CAG repeat diseases. Ann Neurol 52:498–503
Yamada M, Sato T, Tsuji S, Takahashi H (2002) Oligodendrocytic polyglutamine pathology in dentatorubral-pallidoluysian atrophy. Ann Neurol 52:670–674
Yamada M, Tan CF, Inenaga C, Tsuji S, Takahashi H (2004) Sharing of polyglutamine localization by the neuronal nucleus and cytoplasm in CAG-repeat diseases. Neuropathol Appl Neurobiol 30:665–675
Yoo SY, Pennesi ME, Weeber EJ, Xu B, Atkinson R, Chen S, Armstrong DL, Wu SM, Sweatt JD, Zoghbi HY (2003) SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37:383–401
Yvert G, Lindenberg KS, Picaud S, Landwehrmeyer GB, Sahel JA, Mandel JL (2000) Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice. Hum Mol Genet 9:2491–2506
Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–69
Zoghbi HY, Orr HT (1995) Spinocerebellar ataxia type 1. Semin Cell Biol 6:29–35
Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Ann Rev Neurosci 23:217–247
Acknowledgments
We thank S. Egawa, Y. Ohta, C. Tanada, J. Takasaki, N. Kaneko, T. Tanabe and Y. Itou for their technical assistance, and M. Machida and Y. Ueda for their secretarial assistance. This research was supported by a grant from the Research Committee for Ataxic Diseases, the Ministry of Health, Labor and Welfare, Japan, a Grant-in-Aid for Scientific Research (17300109), and a Grant-in-Aid for Scientific Research on Priority Areas-Advanced Brain Project (15016044) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yamada, M., Sato, T., Tsuji, S. et al. CAG repeat disorder models and human neuropathology: similarities and differences. Acta Neuropathol 115, 71–86 (2008). https://doi.org/10.1007/s00401-007-0287-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-007-0287-5