Molecular mechanisms of neurodegeneration

2004 Fiscal Year Final Research Report Summary

• 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)
• Project Period (FY): 2000 – 2004
• Keywords: polyglutamine diseases / nuclear accumulation / transcriptional dysregulation / cAMP-responsive gene / CREB-dependent transcriptional activation / expression profiling / dentatorubral-pallidoluysian atrophy / CAG repeat

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