Molecular mechanisms of neurodegeneration

• Project/Area Number: 12210008
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo (2002-2004); Niigata University (2000-2001)
• Principal Investigator: TSUJI Shoji The University of Tokyo, Graduate School of Medicine, Neurology, Professor, 医学部附属病院, 教授 (70150612)
• Co-Investigator(Kenkyū-buntansha): GOTO Jun The University of Tokyo, Faculty, Lecturer, 医学部附属病院, 講師 (10211252) ; TAKAHASHI Yuji The University of Tokyo, Faculty, Research Associate, 医学部附属病院, 助手 (00372392) ; ONODERA Osamu Niigata University, Brain Research Institute, Associate Professor, 脳研究所, 助教授 (20303167) ; 清水 潤 東京大学, 医学部附属病院, 助手 (40260492) ; 小宅 睦郎 新潟大学, 医学部附属病院, 助手 (70313559) ; 成瀬 聡 新潟大学, 医学部附属病院, 助手 (70313541)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥244,200,000 (Direct Cost: ¥244,200,000); Fiscal Year 2004: ¥59,200,000 (Direct Cost: ¥59,200,000); Fiscal Year 2003: ¥59,200,000 (Direct Cost: ¥59,200,000); Fiscal Year 2002: ¥59,200,000 (Direct Cost: ¥59,200,000); Fiscal Year 2001: ¥66,600,000 (Direct Cost: ¥66,600,000)
• Keywords: polyglutamine diseases / nuclear accumulation / transcriptional dysregulation / cAMP-responsive gene / CREB-dependent transcriptional activation / expression profiling / dentatorubral-pallidoluysian atrophy / CAG repeat / 歯状核赤核・淡倉球ルイ体萎縮症 / neurodegeneration / molecular mechanism / polyglutamine disease / CAG repeat / transcription / animal model / CREB-依存性転写活性化 / c-fos / トランスジェニックマウス / 脊髄小脳変性症 / 遺伝性神経変性疾患 / 転写因子 / 神経細胞死 / TAFII130

Research Abstract

To date, 9 polyglutamine diseases including dentatorubral-pallidoluysian atrophy (DRPLA) have been identified to be caused by abnormal expansion of CAG repeats coding for polyglutamine stretches. To elucidate the molecular mechanisms of neurodegeneration in polyglutamine diseases, we first attempted to create mouse models that closely replicate pathophysiologic processes in human brains. To accomplish this aim, we tried to create transgenic mice carrying a full-length mutant human DRPLA gene as a single copy gene. The Q129 mouse carrying a largely expanded CAG repeats (129) showed strong neurological phenotypes including ataxia, myoclonus and epilepsy. Based on detailed neuropathological analyses, we found that neuronal loss was not detected despite the strong phenotypes, suggesting that neuronal death is not the essential processes in neurodegeneration. We furthermore found that intranuclear accumulation of mutant DRPLA proteins is the essential neuropathological findings. This observ ation raises the possibility that nuclear dysfunction underlies the neurodegeneration in polyglutamine diseases. Based on cell culture systems, we demonstrated that CREB-dependent transcriptional activation is severely suppressed employing a reporter system. We further demonstrated activation of endogenous c-fos transcription is also strongly suppressed by expanded polyglutamine stretches. To further elucidate the mechanisms of transcriptional dysregulation in polyglutamine diseases, we have conducted detailed expression profiling analyses using Q76, Q113 and Q129, carrying a full-length mutant human DRPLA gene as a single copy gene with various lengths of expanded CAG repeats (76, 113 and 129 repeat units). We found that substantial number of genes were suppressed in time-dependent and repeat length-dependent manners. Among the down-regulated genes, many cAMP-responsive genes (c-fos and EGR1) are included Taken together, we have demonstrated that suppression of CREB-dependent transcriptional activation is strongly suppressed by expanded polyglutamine stretches and restoration of such suppression is the target for developing therapeutic approaches for polyglutamine diseases.

Research Products

• [Journal Article] Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches - Augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases (2005)
  • Author(s): Shimohata, M, Shimohata, T, Igarashi, S, Naruse, S, Tsujil, S
  • Journal Title: 1. J. Neurochem 93 Pages: 654-663
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches-Augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases (2005)
  • Author(s): Shimohata, M, Shimohata, T, Igarashi, S, Naruse, S, Tsujii, S.
  • Journal Title: J.Neurochem 93 Pages: 654-663
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Five year follow up of a patient with spinal and bulbar muscular atrophy treated with leuprorelin. (2004)
  • Author(s): Shimohata T, Kimura T, Nishizawa M, Onodera O, Tsuji S
  • Journal Title: J Neurol Neurosurg Psychiatry 75 Pages: 206-207
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein with a potential role as a nucleotide repair protein. (2004)
  • Author(s): Sano, Y., Date, H, Igarashi, S, Onodera, O, Oyake, M, Takahashi, T, Hayashi, S, Morimatsu, M, Takahashi, H, Makifuchi, T, Fukuhara, N, Tsuji, S
  • Journal Title: Ann. Neurol. 55 Pages: 241-249
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. (2004)
  • Author(s): Zuchner S, Mersiyanova, I V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., Jonghe, P D., Takahashi, Y., Tsuji, S., Pericak-Vance, M A., Quattrone, A., Battaloglu, E., Polyakov, AV., Timmerman, V., Schroder, J M., Vance, J M., Battologlu E.
  • Journal Title: Nat Genet 36 Pages: 449-451
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sharing of polyglutamine transport by the neuronal nucleus and cytoplasm in CAG-repeat diseases. (2004)
  • Author(s): Yamada, M, Tan, S-H, Inenaga, C, Tsuji, S, Takahashi, H
  • Journal Title: Neuropathol. Appl. Neurobiol. 30 Pages: 665-675
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The FHA domain of aprataxin (APTX) interacts with the C terminal region of XRCC1. (2004)
  • Author(s): Date, H, Igarashi, S, Sano, Y, Takahashi, T, Takahashi, T, Takano, H, Tsuji, S, Nishizawa, S, Onodera, O
  • Journal Title: Biochem. Biophys. Res. Commun. 325 Pages: 1279-1285
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Five year follow up of a patient with spinal and bulbar muscularatrophy treated with leuprorelin. (2004)
  • Author(s): Shimohata T, Kimura T, Nishizawa M, Onodera 0, Tsuji S.
  • Journal Title: J Neurol Neurosurg Psychiatry 75 Pages: 206-207
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein with a potential role as a nucleotide repair protein. (2004)
  • Author(s): Sano, Y., Date, H, Igarashi, S, Onodera, 0, Oyake, M, Takahashi, T, Hayashi, S, Morimatsu, M, Takahashi, H, Makifuchi, T, Fukuhara, N, Tsuji, S.
  • Journal Title: Ann. Neurol 55 Pages: 241-249
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. (2004)
  • Author(s): Zuchner S, Mersiyanova, I V.Muglia, M.Bissar-Tadmouri, N.Rochelle, J.Dadali, E L.Zappia, M.Nelis, E.Patitucci, A.Senderek, J.Parman, Y.Evgrafov, 0.Jonghe, P D.Takahashi, Y.Tsuji, S.Pericak-Vance, M A.Quattrone, A.Battaloglu, E.Polyakov, AV.Timmerman, V.Schroder, J M.Vance, J M.Battologlu, E.
  • Journal Title: Nat Genet 36 Pages: 449-451
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sharing of polyglutamine transport by the neuronal nucleus and cytoplasm in CAG-repeat diseases. (2004)
  • Author(s): Yamada, M, Tan, S-H, Inenaga, C, Tsuji, S, Takahashi, H.
  • Journal Title: Neuropathol.Appl.Neurobiol 30 Pages: 665-675
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The FHA domain of aprataxin (APTX) interacts with The C terminal region of XRCC1. (2004)
  • Author(s): Date, H, Igarashi, S, Sano, Y, Takahashi, T, Takahashi, T, Takano, H, Tsuji, S, Nishizawa, S, Onodera, 0.
  • Journal Title: Biochem.Biophys.Res.Commun. 325 Pages: 1279-1285
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Five year follow up of a patient with spinal and bulbar muscular atrophy treated with leuprorelin. (2004)
  • Author(s): Shimohata T, Kimura T, Nishizawa M, Onodera O, Tsuji S.
  • Journal Title: J Neurol Neurosurg Psychiatry 75 Pages: 206-207
• [Journal Article] Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein wi (2004)
  • Author(s): Sano, Y., Date, H, Igarashi, S, Onodera, O, Oyake, M, Takahashi, T, Hayashi, S, Morimatsu, M, Takahashi, H, Makifuchi, T, Fukuhara, N, Tsuji, S.
  • Journal Title: Ann.Neurol. 55 Pages: 241-249
• [Journal Article] Mutations in the mitochondrial GTPase mito fusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. (2004)
  • Author(s): Zuchner S, Mersiyanova, I V.Muglia, M.Bissar-Tadmouri, N.Rochelle, J.Dadali, E L.Zappia, M.Nelis, E.Patitucci, A.Senderek, J.Parman, Y.Evgrafov, O.Jonghe, P D.Takahashi, Y.Tsuji, S.Pericak-Vance, M A.Quattrone, A.Battaloglu, E.Polyakov, A V.Timmerman, V.Schroder, J M.Vance, J M.Battologlu, E.
  • Journal Title: Nat Genet 36 Pages: 449-451
• [Journal Article] Sharing of polyglutamine transport by the neuronal nucleus and cytoplasm in CAG-repeat diseases. (2004)
  • Author(s): Yamada, M, Tan, S-H, Inenaga, C, Tsuji, S, Takahashi, H.
  • Journal Title: Neuropathol.Appl.Neurobiol. 30 Pages: 665-675
• [Journal Article] The FHA domain of aprataxin (APTX) interacts with the C terminal region of XRCC1. (2004)
  • Author(s): Date, H, Igarashi, S, Sano, Y, Takahashi, T, Takahashi, T, Takano, H, Tsuji, S, Nishizawa, S, Onodera, O.
  • Journal Title: Biochem.Biophys.Res.Commun. 325 Pages: 1279-1285
• [Journal Article] Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches - Augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases
  • Author(s): Shimohata, M, Shimohata, T, Igarashi, S, Naruse, S, Tsujil, S.
  • Journal Title: 1.J.Neurochem (in press)
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• [Publications] Sano, Y., Date, H, Igarashi, et al.: "Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein with a potential role as a nucleotide"Ann.Neurol. 55. 241-249 (2004)
• [Publications] Hara, K, Fukushima, et al.: "Japanese SCA families with a distinct phenotype linked to a locus overlapping with SCA15 locus"Neurol.. 62. 648-651 (2004)
• [Publications] Tsuji, S.: "Spinocerebellar ataxia type 17(SCA17)-latest member of polyglutamine diseases highlights unanswered questions-"Arch.Neurol.. (in press).
• [Publications] Yamada, M, Tan, S-H., et al.: "Sharing of polyglutamine transport by the neuronal nucleus and cytoplasm in CAG-repeat diseases"Neuropathol.Appl.Neurobiol.. (in press).
• [Publications] Sanpei K, Ikeuchi T, Tsuji S: "DIRECT technologies for molecular cloning of genes containing expanded CAG repeats"Methods in Molecular Biology. 217. 73-81 (2003)
• [Publications] Funayama, M., Hasegawa, K., et al.: "A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1"Annals of Neurology. 51・3. 296-301 (2002)
• [Publications] Takahashi T., Igarashi S., et al.: "Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene"J. Neurol. Neurosurg. Psychiat.. 72. 675-680 (2002)
• [Publications] Toyoshima, I., Sugawara, M., et al.: "Time course of polyglutamine aggregate body formation and cell death : Enhanced growth in nucleus and an interval for cell death"Journal of Neuroscience Research. 68. 442-448 (2002)
• [Publications] Shimohata, T., Sato, A., et al.: "Expanded polyglutamine stretchers form an 'aggresome'"Neuroscience letters. 323. 215-218 (2002)
• [Publications] Arai, A., Tanaka, K., et al.: "A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees"Ann Neurol. 52. 516-519 (2002)
• [Publications] Silveria, I., Miranda, C., et al.: "Trinucleotide repeats in 202 families with ataxia. A small expanded(CAG)n allele at the SCA17 locus"Arch Neurol. 59. 623-629 (2002)
• [Publications] Yamada, M.: "Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy"Ann.Neurol.. 49. 14-23 (2001)
• [Publications] Gaspar, C.: "Ancestral origins of the Machado-Joseph disease mutation : A Worldwide haplotype study"Am.J.Hum.Genet.. 68・2. 523-528 (2001)
• [Publications] Yamada, M.: "Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph disease"Acta Neuropathol.. 101. 140-144 (2001)
• [Publications] Shimohata, T.: "Expanded polyglutamine stretches lead to aberrant transcriptional regulation in polyglutamine diseases"Human Cell. 14・1. 17-25 (2001)
• [Publications] Zhao, C.: "Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIFIB β"Cell. 105. 587-597 (2001)
• [Publications] Nakamura, K.: "SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein"Human Molecular Genetics. 10・14. 1441-1448 (2001)
• [Publications] Adachi, N.: "Dentatorubral-Pallidoluysian Atrophy (DRPLA) presenting with psychosis"The Journal of Neuropsychiatry and Clinical Neurosciences. 13. 258-260 (2001)
• [Publications] Date, H.: "Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene"Nature Genetics:184-188,2001. 29. 184-188 (2001)
• [Publications] Yamada, M.: "Interaction between neuronal intranuclear inclusions and promyelocytic leukemia protein nuclear and coiled bodies in CAG repeat diseases"American Journal of Pathology. 159・5. 1785-1795 (2001)
• [Publications] Takahashi T.: "Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNAIA gene"J.Neurol.Neurosurg.Psychiat. (in press).
• [Publications] Shibasaki,Y., et al.: "Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15q13-15."Ann.Neurol.. 48. 108-112 (2000)
• [Publications] Yamashita,I., et al.: "A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter."Ann.Neurol.. 48. 156-163 (2000)
• [Publications] Maruyama,M., et al.: "Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism."Ann.Neurol.. 48. 245-250 (2000)
• [Publications] Takano,H., et al.: "Mutational analysis of X-linked adrenoleukodystrophy gene."Cell Biochem.Biophys.. 32. 177-185 (2000)
• [Publications] Shimohata,T., et al.: "Expanded polyglutamine stretches associated with CAG repeat diseases interact with TAFII130, interfering with CREB-dependent transcription."Nature Genet.. 26. 29-35 (2000)
• [Publications] Saito,M., et al.: "Autosomal recessive juvenile parkinsonism."Brain Dev.. 22(Suppl.1). S115-S117 (2000)