Interaction, posttranslational modification, and subcellular localization of proteins causative for neurodegenerative diseases

• Project/Area Number: 21591097
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kinki University (2010-2011); Nara Medical University (2009)
• Principal Investigator: HIRANO Makito 近畿大学, 医学部・附属病院, 准教授 (50347548)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 翻訳後修飾 / 神経変性疾患 / 蛋白相互作用 / 細胞内局在 / 翻訳後修復

Research Abstract

The objective of this work is to investigate interaction, posttranslational modification, and subcellular localization of proteins causative for neurodegenerative diseases. Posttranslational modification includes phosphorylation and ubiquitination. In this study, we found protein kinase Cγ, the protein causative for autosomal dominant spinocerebellar ataxia type 14(SCA14), phospholyated aprataxin, the protein causative for autosomal recessive ataxia. This phosphorylation inhibited the nuclear transport of aprataxin that has a DNA repair activity, resulting in its deficiency in the nucleus, accumulation of DNA damage unrepaired, and neuronal cell death(Hum Mol Genet 2009 ; 18 : 3533). We identified ubiquilin2 as a novel protein causative for X-linked dominant amyotrophic lateral sclerosis(ALS). This protein co-aggregates with TDP43, FUS, and optineurin, proteins causative for other types of ALS, in ubiquitin-positive inclusions of motor neurons of patients with familial and even sporadic ALS(Nature 2011 ; 477 : 211).

Research Products

• [Journal Article] Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onsetALS and ALS/dementia (2011)
  • Author(s): Deng, H. X., Chen, W., Hong, S. T., Boycott, K. M., Gorrie, G. H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G. H., Donkervoort, S., Bigio, E. H., Brooks, B. R., Ajroud, K., Sufit, R. L., Haines
  • Journal Title: Nature Volume: 477 Issue: 7363 Pages: 211-215
  • DOI: 10.1038/nature10353
  • Peer Reviewed
• [Journal Article] Assembly defect due to a PSMB8 mutation reduces proteasome activity and causes the autoinflammatory disorder, Nakajo-Nishimura syndrome (2011)
  • Author(s): Arima, K., Kinoshita, A., Mishima, H., Kanazawa, N., Kaneko, T., Mizushima, T., Ichinose, K., Nakamura, H., Tsujino, A., Kawakami, A., Matsunaka, M., Kasagi, S., Kawano, S., Kumagai, S., Ohmura, K., Mimori, T., Hirano, M., Ueno, S., Tanaka, K., Tanaka, M., Toyoshima, I., Sugino, H., Yamakawa, A., Tanaka, K., Niikawa, N., Furukawa, F., Murata, S., Eguchi, K., Ida, H., Yoshiura, K.
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 108 Issue: 36 Pages: 14914-14919
  • DOI: 10.1073/pnas.1106015108
  • Peer Reviewed
• [Journal Article] Risks of inappropriate secretion of antidiuretic hormone in multiple system atrophy (2011)
  • Author(s): Samukawa, M., Hirano, M., Sakamoto, H., Kitada, M., Kusunoki, S. and Nakamura, Y
  • Journal Title: Mov. Disord Volume: 26 Issue: 14 Pages: 2572-2573
  • DOI: 10.1002/mds.23904
  • Peer Reviewed
• [Journal Article] A novel mutation in the calcium channel gene in a family with hypokalemic periodic paralysis (2011)
  • Author(s): Hirano, M., Kokunai, Y., Nagai, A., Nakamura, Y., Saigoh, K., Kusunoki, S. and Takahashi, M. P
  • Journal Title: J. Neurol. Sci Volume: 309 Issue: 1-2 Pages: 9-11
  • DOI: 10.1016/j.jns.2011.07.046
  • Peer Reviewed
• [Journal Article] 遺伝性脊髄小脳変性症への言語聴覚療法-長期介入報告- (2011)
  • Author(s): 磯野千春, 中村雄作, 阪本光, 平野牧人, 山田郁子
  • Journal Title: 言語聴覚研究 Volume: 8 Pages: 63-65
  • Peer Reviewed
• [Journal Article] Abnormal cystatin C levels in two patients with Bardet-Biedl syndrome (2011)
  • Author(s): Hirano M, et al.
  • Journal Title: Clin Med Cas Rep Ins Volume: (in press)
  • Peer Reviewed
• [Journal Article] Naturally-and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism (2010)
  • Author(s): Asai, H., Hirano, M., Kiriyama, T., Ikeda, M. and Ueno, S
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 391 Issue: 1 Pages: 800-805
  • DOI: 10.1016/j.bbrc.2009.11.141
  • Peer Reviewed
• [Journal Article] Spontaneous and experimental exon skipping restors the Parkin genedeficits in autosomal recessive Juvenile parkinsonism. (2010)
  • Author(s): Asai H, et al.
  • Journal Title: Ann Neurol Volume: 68
  • Peer Reviewed
• [Journal Article] The first nationwide survey of triple A syndrome in Japan (2010)
  • Author(s): Hirano M, et al.
  • Journal Title: Ann Neurol Volume: 68
  • Peer Reviewed
• [Journal Article] 認知症診療の未来を考える (2010)
  • Author(s): 花田一志、田中敬剛、平野牧人, 他3名
  • Journal Title: Japan Medicine Monthly Volume: 11 Pages: 6-9
• [Journal Article] Naturally-and experimentally-designed restorations of the Parkin gene deficit 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] 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. and Ueno, S
  • Journal Title: Hum. Mol. Genet Volume: 18 Issue: 19 Pages: 3533-3543
  • DOI: 10.1093/hmg/ddp298
  • Peer Reviewed
• [Journal Article] Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease (2009)
  • Author(s): Asai, H., Hirano, M., Furiya, Y., Udaka, F., Morikawa, M., Kanbayashi, T., Shimizu, T. and Ueno, S
  • Journal Title: Clin. Neurol. Neurosurg Volume: 111 Issue: 4 Pages: 341-344
  • DOI: 10.1016/j.clineuro.2008.11.007
  • 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
• [Presentation] SCA3およびSCA6における嚥下障害の経過と特徴 (2011)
  • Author(s): 磯野千春, ら
  • Organizer: 第29回日本神経治療学会
  • Place of Presentation: フェニックス・プラザ(福井市)
  • Year and Date: 2011-11-17
• [Presentation] UBQLN2は筋萎縮性側索硬化症の新規原因遺伝子である (2011)
  • Author(s): 平野牧人, ら
  • Organizer: 第56回日本人類遺伝学会
  • Place of Presentation: 幕張メッセ(千葉市)
  • Year and Date: 2011-11-12
• [Presentation] The first nationwide survey of Bardet-Biedl syndrome in Japan (2011)
  • Author(s): Hirano M, et al
  • Organizer: 136th Annual meeting of American Neurological Association
  • Place of Presentation: Manchester Grand Hyatt (San Diego, USA)
  • Year and Date: 2011-09-26
• [Presentation] バルデー・ビードル症候群の全国実態調査 (2011)
  • Author(s): 平野牧人, ら
  • Organizer: 第52回日本神経学会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2011-05-20
• [Presentation] 多系統萎縮症と抗利尿ホルモン不適合分泌症候群の関連 (2011)
  • Author(s): 阪本光, ら
  • Organizer: 第52回日本神経学会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2011-05-18
• [Presentation] Oxidative stress-induced DNA damage in neurodegenerative diseases-autosomal dominant and recessive ataxia and motor neuron diseases- (2011)
  • Author(s): Hirano M, 他3名
  • Organizer: 1^<st> RIRBM International Symposium Genome damage and non-cancerous diseases
  • Place of Presentation: 広島
  • Year and Date: 2011-03-03
• [Presentation] Oxidative stress-induced DNA damage in neurodegenerative diseases-autosomal dominant and recessive ataxia and motor neuron diseases- (2011)
  • Author(s): Hirano, M., 他
  • Organizer: 1^<st> RIRBM International Symposium Genome damage and non-cancerous diseases
  • Place of Presentation: Hiroshima
• [Presentation] The first nationwide survey of Bardet-Biedl syndrome in Japan (2011)
  • Author(s): Hirano, M., 他
  • Organizer: 136th Annual meeting of American Neurological Association
  • Place of Presentation: San Diego, USA
• [Presentation] SCA3およびSCA6における嚥下障害の経過と特徴 (2011)
  • Author(s): 平野牧人, 他
  • Organizer: 第29回日本神経治療学会
  • Place of Presentation: 福井
• [Presentation] UBQLN2は筋萎縮性側索硬化症の新規原因遺伝子である (2011)
  • Author(s): 平野牧人, 他
  • Organizer: 第56回日本人類遺伝学会
  • Place of Presentation: 大宮
• [Presentation] バルデー・ビードル症候群の全国実態調査 (2011)
  • Author(s): 平野牧人, 他
  • Organizer: 第35回日本遺伝カウンセリング学会
  • Place of Presentation: 京都
• [Presentation] 多系統萎縮症と抗利尿ホルモン不適合分泌症候群の関連 (2011)
  • Author(s): 平野牧人, 他
  • Organizer: 第52回日本神経学会
  • Place of Presentation: 名古屋
• [Presentation] 本邦におけるバルデー・ビードル症候群の実態 (2011)
  • Author(s): 平野牧人, 他
  • Organizer: 第52回日本神経学会
  • Place of Presentation: 名古屋
• [Presentation] Phenotype-genotype relationship of triple A syndrome (2010)
  • Author(s): Ikeda M, 他6名
  • Organizer: 136^<th> Annual meeting of American Neurological Association
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2010-09-13
• [Presentation] パーキン関連パーキンソニズムにおけるエクソンスキッピング誘導療法 (2010)
  • Author(s): 浅井宏英, 他4名
  • Organizer: 第28回日本神経治療学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2010-07-15
• [Presentation] 常染色体劣性遺伝パーキンソニズムの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, 他4名
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-20
• [Presentation] The first nationwide survey of triple A syndrome in Japan (2010)
  • Author(s): Hirano, M., 他
  • Organizer: 135th Annual meeting of American Neurological Association
  • Place of Presentation: San Francisco, USA
• [Presentation] Phenotype-Genotype Relationship of Triple A Syndrome (2010)
  • Author(s): Hirano, M., 他
  • Organizer: 135th Annual meeting of American Neurological Association
  • Place of Presentation: San Francisco, USA
• [Presentation] The influence of antihypertensive drugs, rennin-angiotensin blockades, on cognitive decline and insulin resistance in Alzheimer's disease (2010)
  • Author(s): Hirano, M., 他
  • Organizer: 135th Annual meeting of American Neurological Association
  • Place of Presentation: San Francisco, USA
• [Presentation] Spontaneous and Experimental Exon Skipping Restores the Parkin Gene Deficits in Autosomal Recessive Juvenile Parkinsonism (2010)
  • Author(s): Hirano, M., 他
  • Organizer: 135th Annual meeting of American Neurological Association
  • Place of Presentation: San Francisco, USA
• [Presentation] Japanese patients with Bardet-Biedl syndrome (2010)
  • Author(s): Hirano, M., 他
  • Organizer: Neuro2010(日本神経化学会総会)
  • Place of Presentation: 神戸
• [Presentation] 運動ニューロン病様AAA症候群の全国実態調査および臨床遺伝学的研究連 (2010)
  • Author(s): 平野牧人, 他
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] Alzheimer患者における内臓脂肪面積とadipocytokinesの検討 (2010)
  • Author(s): 平野牧人, 他
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 常染色体劣性パーキンソニズムのparkin機能欠損に対するアンチセンス治療の検討 (2010)
  • Author(s): 平野牧人, 他
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 本邦におけるバルデー・ビードル症候群 (2010)
  • Author(s): 平野牧人, 他
  • Organizer: 人類遺伝学会第55回大会
  • Place of Presentation: 大宮
• [Presentation] 多系統萎縮症における抗利尿ホルモン不適合分泌症候群の合併 (2010)
  • Author(s): 平野牧人, 他
  • Organizer: 第63回日本自律神経学会総会
  • Place of Presentation: 横浜
• [Presentation] FUS関連筋萎縮側索硬化症細胞の酸化ストレスに対する脆弱性とDNA損傷の蓄積 (2010)
  • Author(s): 平野牧人, 他
  • Organizer: 第53回放射線影響学会
  • Place of Presentation: 京都
• [Presentation] パーキン関連パーキンソニズムにおけるエクソンスキッピング誘導療法 (2010)
  • Author(s): 平野牧人, 他
  • Organizer: 第28回日本神経治療学会
  • Place of Presentation: 横浜
• [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 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, 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, 他
  • Organizer: 日本放射線影響学会
  • Place of Presentation: 広島
• [Presentation] Japanese patients with triple A syndrome (2009)
  • Author(s): Hirano, M., 他
  • Organizer: 6th Congress of International Society for Autonimic Neuroscience
  • Place of Presentation: Sydney, Australia
• [Presentation] Aggregate formation and activities of mutant protein kinase C gamma, a protein causative for spinocerebellar ataxia type 14 (2009)
  • Author(s): Hirano, M., 他
  • Organizer: 134th Annual meeting of American Neurological Association
  • Place of Presentation: Baltimore, USA
• [Presentation] MRI abnormalities of cervical roots in hereditary neuropahty with liability to pressure palsies (2009)
  • Author(s): Hirano, M., 他
  • Organizer: 134th Annual meeting of American Neurological Association
  • Place of Presentation: Baltimore, USA
• [Presentation] Kinase activities of muta nt protein kinase C gamma, a protein cau sative for spinocerebellar ataxia type 14, and neuronal cell death under oxidative st ress (2009)
  • Author(s): Hirano, M., 他
  • Organizer: 134th Annual meeting of American Neurological Association
  • Place of Presentation: Baltimore, USA
• [Presentation] 遺伝性脊髄小脳変性症14型の原因となる変異protein kinase Cg活性と蛋白凝集の関連 (2009)
  • Author(s): 平野牧人, 他
  • Organizer: 第50回日本神経学会
  • 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): 平野牧人, 他
  • Organizer: 第50回日本神経学会
  • Place of Presentation: 仙台
• [Presentation] Alzheimer患者におけるメタボリックシンドロームと内臓脂肪面積の検討 (2009)
  • Author(s): 平野牧人, 他
  • Organizer: 第50回日本神経学会
  • Place of Presentation: 仙台
• [Presentation] PMP22遺伝子欠失を伴う遺伝性圧脆弱性ニューパチーにおける神経根のMRI所見 (2009)
  • Author(s): 平野牧人, 他
  • Organizer: 第50回日本神経学会
  • 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): 平野牧人, 他
  • Organizer: 第50回日本神経学会
  • Place of Presentation: 仙台