Repairing DNA damages in neurodegenerative diseases

• Project/Area Number: 20591008
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nara Medical University
• Principal Investigator: UENO Satoshi Nara Medical University, 医学部, 教授 (40184949)
• Co-Investigator(Kenkyū-buntansha): MORI Toshio 奈良県立医科大学, 医学部, 研究教授 (10115280) ; HIRANO Makito 近畿大学, 医学部付属病院, 准教授 (50347548)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 臨床神経分子遺伝学 / DNA修復 / 神経変性疾患 / 酸化的ストレス / 中心体 / Parkin

Research Abstract

Parkin gene mutant failed to ubiquitinate cyclin E, leading to cell cycle deregulation. We has uncovered the nuclear pathway by which the Parkin mutant ubiqutinates cyclin E and may thus control the cell cycle, contributing to cell survival. Our observations may provide a molecular basis for the development of an antisense-mediated therapeutic procedure that would be specific, rational, and genetically based. In spinocerebellar ataxia (SCA14), causative gene mutant ProteinkinaseCγcaused to inhibit the nuclear entry of recessive-ataxia-related aprataxin. Decreased nuclear aprataxin increased oxidative stress-induced DNA damage and cell death.

Research Products

• [Journal Article] Naturally- and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism. (2010)
  • Author(s): H.Asai, et al
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 391 Pages: 800-805
  • Peer Reviewed
• [Journal Article] Naturally- and experimentally-designed restorations of the Parkin genedeficit in autosomal recessive juvenile parkinsonism (2010)
  • Author(s): Asai H, et al.
  • Journal Title: Biochem Biophys Res Commnun 391 Pages: 800-805
  • Peer Reviewed
• [Journal Article] Naturally-and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism. (2009)
  • Author(s): Asai H, Hirano M, Kiriyama T, Ikeda M, Ueno S
  • Journal Title: Biochem Biophys Res Commun,Epub 1;391(1),Nov 27 Pages: 800-805
• [Journal Article] Protein kinase C gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin. (2009)
  • Author(s): Asai H, Hirano M, Shimada K, Kiriyama T, Furiya Y, Ikeda M, Iwamoto T, Mori T, Nishinaka K, Konishi N, Udaka F, Ueno S
  • Journal Title: Hum Mol Genet,Epub 1;18(19) Pages: 3533-3543
• [Journal Article] 総説 神経疾患と塩基除去修復 (2009)
  • Author(s): 平野牧人、森俊雄、上野聡
  • Journal Title: 放射線生物研究 44巻 Pages: 285-293
  • Peer Reviewed
• [Journal Article] Protein kinase C gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin (2009)
  • Author(s): Asai H, et al.
  • Journal Title: Hum Mol Genet 18 Pages: 3533-3543
  • Peer Reviewed
• [Journal Article] Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease (2009)
  • Author(s): Asai H, et al.
  • Journal Title: Clin Neurol Neurosurg 111 Pages: 341-344
  • Peer Reviewed
• [Journal Article] 総説 神経疾患と塩基除去修復 (2009)
  • Author(s): 平野牧人, 森俊雄, 上野聡
  • Journal Title: 放射線生物研究 44 Pages: 285-293
  • Peer Reviewed
• [Journal Article] Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach. (2008)
  • Author(s): Deng HX, Jiang H, Fu R, Zhai H, Shi Y, Liu E, Hirano M, Dal Canto MC, Siddique T.
  • Journal Title: Hum Mol Genet,Epub,Erratum in: Hum Mol Genet. 17(15),1;18(3)
  • Peer Reviewed
• [Journal Article] Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress. (2008)
  • Author(s): Kiriyama T, Hirano M, Asai H, Ikeda M, Furiya Y, Ueno S
  • Journal Title: Biochem Biolphys Res Commnun 374 Pages: 631-634
  • Peer Reviewed
• [Journal Article] Comparative study of nucleotide excision repair defects between XPD-mutated fibroblasts derived from trichothiodystrophy and xeroderma pigmentosum patients. (2008)
  • Author(s): Nishiwaki T, Kobayashi N, Iwamoto T, Yamamoto A, Sugiura S, Liu YC, Sarasin A, Okahashi Y, Hirano M, Ueno S, Mori T
  • Journal Title: DNA repair 7 Pages: 1990-1998
  • Peer Reviewed
• [Journal Article] Identification of a nuclear localization signal of XRCC1 overcoming impaired nuclear import in triple A syndrome. (2008)
  • Author(s): Kiriyama T, Hirano M, Asai H, Furiya Y, Kanbayashi T, Ikeda M, Ueno S
  • Journal Title: Ann Neurol 64
  • Peer Reviewed
• [Journal Article] Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease. (2008)
  • Author(s): Asai H, Hirano M, Furiya Y, Udaka F, Morikawa M, Kanbayashi T, Shimizu T, Ueno S
  • Journal Title: Clin Neurol Neurosurg 111(4) Pages: 341-344
  • Peer Reviewed
• [Journal Article] Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress. (2008)
  • Author(s): Kiriyama T, et al.
  • Journal Title: Biochem Biophys Res Commnun 374 Pages: 631-634
  • Peer Reviewed
• [Journal Article] Comparative study of nucieotide excision repair defects between XPD-mutated fibroblasts derived from trichothiodystrophy and xeroderma pigmentosum patients. (2008)
  • Author(s): Nishiwaki T, et al.
  • Journal Title: DNA repair 7 Pages: 1990-1998
  • Peer Reviewed
• [Journal Article] Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach (2008)
  • Author(s): Deng H-X, et al.
  • Journal Title: Hum Mol Genet 17 Pages: 2310-2319
  • Peer Reviewed
• [Journal Article] Identification of nuclear localization signal of XRCC1 overcoming impaired nuclear import in triple A syndrome. (2008)
  • Author(s): Kiriyama T, et al.
  • Journal Title: Ann Neurol 64
  • Peer Reviewed
• [Journal Article] 総説 神経疾患と塩基除去修復
  • Author(s): 平野牧人, 森 俊雄, 上野 聡
  • Journal Title: 放射線生物研究 (印刷中)
  • Peer Reviewed
• [Presentation] Spontaneous and Experimental Exon Skipping Restores the Parkin Gene Deficits in Autosomal Recessive Juvenile Parkinsonism (2011)
  • Author(s): 浅井宏英, 他
  • Organizer: 135^<th> Annual Meeting of the American Neurological Association
  • Place of Presentation: San.Francisco, U.S.A
• [Presentation] 常染色体劣性遺伝パーキンソンニズムのparkin機能欠損に対するアンチセンス治療の検討 (2010)
  • Author(s): 浅井宏英、平野牧人、桐山敬生、池田真徳、上野聡
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-20
• [Presentation] Spontaneous and Experimental Exon Skipping Restores the Parkin Gene Deficits in Autosomal Recessive Juvenile Parkinsonism. (2010)
  • Author(s): Asai H, Hirano M, Kiriyama T, Ikeda M, Horikawa H, Ueno S
  • Organizer: 135^<th> Annual Meeting of the American Neurological Association
  • Place of Presentation: San Francisco, U.S.A
• [Presentation] DNA単鎖切断修復蛋白アプラタキシンと神経疾患～常染色体優性・劣性小脳失調症とAAA症候群～ (2009)
  • Author(s): 平野牧人, 他6名
  • Organizer: 第52回放射線影響学会
  • Place of Presentation: 広島
  • Year and Date: 2009-11-11
• [Presentation] Aggregate formation and activities of mutant protein kinase C gamma, a protein causative for spinocerebellar ataxia type 14 (2009)
  • Author(s): 平野牧人, 他5名
  • Organizer: 135^<th> Annual meeting of American Neurological Association
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2009-10-13
• [Presentation] Kinase activities of mutant protein knase C gamma, a protein causative for spinocerebellar ataxia type 14, and neuronal cell death underoxidative stress (2009)
  • Author(s): 浅井宏英, 他5名
  • Organizer: 135^<th> Annual meeting of American Neurological Association
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2009-10-13
• [Presentation] 遺伝性脊髄小脳変性症14型の原因となる 変異 protein kinase Cγ活性と蛋白凝集の関連 (2009)
  • Author(s): 平野牧人, 他5名
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-21
• [Presentation] 酸化ストレス下における遺伝性脊髄小脳変性症14型の原因となる変異 protein kinase Cγ活性と細胞死の関連 (2009)
  • Author(s): 浅井宏英, 他5名
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-20
• [Presentation] DNA修復蛋白XRCC1の核局在シグナルを用いた Aprataxin とSOD1の核内輸送 (2009)
  • Author(s): 桐山敬生, 他5名
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-20
• [Presentation] DNA単鎖切断修復蛋白アプラタキシンと神経疾患.常染色体優性・劣性小脳失調症とAAA症候群 (2009)
  • Author(s): 平野牧人、森俊雄、池田真徳、浅井宏英、桐山敬生、降矢芳子、上野聡
  • Organizer: 第52回日本放射線影響学会大会
  • Place of Presentation: 広島
• [Presentation] Kinase activities of mutant protein kinase C gamma, a protein causative for spinocerebellar ataxia type 14, and neuronal cell death under oxidative stress. (2009)
  • Author(s): 浅井宏英, 平野牧人, 池田真徳, 上野聡
  • Organizer: The 134th Annual Meeting of American Neurological Association
  • Place of Presentation: Baltimore
• [Presentation] Aggregate formation and activities of mutant protein kinase C gamma, a protein causative for spinocerebellar ataxia type 14. (2009)
  • Author(s): 平野牧人, 浅井宏英, 桐山敬生, 池田真徳, 降矢芳子, 上野聡
  • Organizer: The 134th Annual Meeting of American Neurological Association
  • Place of Presentation: Baltimore
• [Presentation] 遺伝性脊髄小脳変性症14型の原因となる変異protein kinase Cγ活性と蛋白凝集の関連 (2009)
  • Author(s): 平野牧人, 浅井宏英, 桐山敬生, 池田真徳, 降矢芳子, 上野聡
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Presentation] DNA修復蛋白XRCC1の核局在シグナルを用いたAprataxinとSOD1の核内輸送 (2009)
  • Author(s): 桐山敬生、平野牧人、浅井宏英、池田真徳、降矢芳子、上野聡
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Presentation] 酸化ストレス下における遺伝性脊髄小脳変性症14型の原因となる 変異protein kinase Cγ活性と細胞死の関連 (2009)
  • Author(s): 浅井宏英、平野牧人、桐山敬生、池田真徳、降矢芳子、上野聡
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Presentation] 酸化的DNA損傷修復系への小脳失調原因蛋白アプラタキシンの機能的関与 (2008)
  • Author(s): 平野牧人, 他7名
  • Organizer: 第48回放射線影響学会
  • Place of Presentation: 小倉
  • Year and Date: 2008-11-20
• [Presentation] In vivo DNA damage accumulation in aprataxin-related ataxia. (2008)
  • Author(s): Hirano M, 他9名
  • Organizer: 134^<th> Annual meeting of American Neurological Association
  • Place of Presentation: Salt Lake City, USA
  • Year and Date: 2008-09-23
• [Presentation] 眼球運動失行と低アルブミン血症を伴う早発型脊髄小脳失調症におけるDNA損傷の蓄積 (2008)
  • Author(s): 平野牧人, 上野聡, 他7名
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-16
• [Presentation] 酸化的DNA損傷修復系への小脳失調原因蛋白アプラタキシンの機能的関与 (2008)
  • Author(s): 平野牧人、浅井宏英、桐山敬生、池田真徳、降矢芳子、森俊雄、安井明、上野聡
  • Organizer: 第51回日本放射線影響学会
  • Place of Presentation: 小倉
• [Presentation] In Vivo DNA Damage Accumulation in Aprataxin-Related Ataxia. (2008)
  • Author(s): Hirano M, Asai H, Aoki M, shimada K, Fuiya Y, Kiriyama T, Ikeda M, Konishi N, Itoyama Y, Ueno S
  • Organizer: 133rd Annual Meeting of the American Neurological Association
  • Place of Presentation: Salt Lake City, UT
• [Book] 医療の最先端-奈良医大からの発信- (2008)
  • Author(s): 上野聡, 平野牧人, 他41名
  • Total Pages: 208
  • Publisher: 創元社
• [Book] 医療の最先端-奈良医大からの発信- (2008)
  • Author(s): 上野 聡, 他42名
  • Total Pages: 208
  • Publisher: 創元社