Therapeutic protein degradation and relationship between p62 and ubiquilin 2, new proteins causative for neurodegenerative diseases

• Project/Area Number: 25461297
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kinki University
• Principal Investigator: HIRANO Makito 近畿大学, 医学部附属病院, 准教授 (50347548)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: p62 / オートファジー / iPS細胞 / 神経細胞 / 筋萎縮性側索硬化症 / 人工多能性幹細胞 / ubiquiliin2

Outline of Final Research Achievements

This study was conducted to clarify ubiquilin 2, a novel amyotrophic lateral sclerosis (ALS)-related protein that the research manager helped to identify, and p62 of which mutations in the first Japanese patients were found by the manager. We used pluripotent stem (iPS) cells of patients with ALS and controls. We found neurons derived from iPS cells of a patient with a p62 mutation had aggregations of p62, a pathological hallmark of ALS. However, the aggregates were not positive for ubiquilin 2 or valosin-containing protein (VCP). Control neurons were negative for p62. Cells of a p62-negative patient had mild aggregations. Treatment of an autophagy-inducer and an antioxidant reduced aggregation.

Research Products

• [Journal Article] 日本のValosin-containing protein関連筋萎縮性側索硬化症 (2016)
  • Author(s): 平野牧人、中村雄作、楠 進
  • Journal Title: 臨床神経学 Volume: 印刷中
  • NAID: 130005149740
  • Peer Reviewed
• [Journal Article] ALSとSQSTM1 (2015)
  • Author(s): 平野牧人
  • Journal Title: 神経内科 Volume: 82 Pages: 360-365
• [Journal Article] VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation (2015)
  • Author(s): Hirano M, Nakamura Y, Saigoh K, Sakamoto H, Ueno S, Isono C, Mitsui Y, Kusunoki S.
  • Journal Title: Neurobiol Aging Volume: 36 Issue: 3 Pages: 1604.e1-1604.e6
  • DOI: 10.1016/j.neurobiolaging.2014.10.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The first nationwide survey and genetic analyses of Bardet-Biedl syndrome in Japan (2015)
  • Author(s): Hirano M, Satake W, Ihara K, Tsug I, Kondo S, Saida K, Betsui H, Okubo K, Sakamoto H, Ueno S, Ikuno Y, Ishihara R, Iwahashi H, Ohishi M, Mano T, Yamashita T, Suzuki Y, Nakamura Y, Kusunoki S, Toda T
  • Journal Title: PLOS ONE Volume: 10 Issue: 9 Pages: e0136317-e0136317
  • DOI: 10.1371/journal.pone.0136317
  • Peer Reviewed / Open Access
• [Journal Article] Rotigotine Transdermal Patch Improves Swallowing in Dysphagic Patients with Parkinson's Disease. (2015)
  • Author(s): Hirano M, Isono C, Sakamoto H, Ueno S, Kusunoki S, Nakamura Y.
  • Journal Title: Dysphagia Volume: 30 Issue: 4 Pages: 452-426
  • DOI: 10.1007/s00455-015-9622-5
  • Peer Reviewed
• [Journal Article] Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems (2015)
  • Author(s): Isono C, Hirano M, Sakamoto H, Ueno S, Kusunoki S, Nakamura Y.
  • Journal Title: Eur Neurol Volume: 74 Issue: 5-6 Pages: 237-242
  • DOI: 10.1159/000442252
  • Peer Reviewed
• [Journal Article] The first Japanese familial case of spinocerebellar ataxia 23 with a novel mutation in the PDYN gene (2015)
  • Author(s): 1.Saigoh K, Mitsui J, Hirano, M, Sioyama M, Samukawa M, Ichikawa Y, Goto J, Tsuji S, Kusunoki S
  • Journal Title: Parkinsonism Relat Disord Volume: 21 Issue: 3 Pages: 332-334
  • DOI: 10.1016/j.parkreldis.2014.12.028
  • Peer Reviewed
• [Journal Article] Binding specificity of anti-HNK-1 IgM M-protein in anti-MAG neuropathy: Possible clinical relevance. (2015)
  • Author(s): Hamada Y, Hirano M, Kuwahara M, Samukawa M, Takada K, Morise J, Yabuno K, Oka S, and Kusunoki S.
  • Journal Title: Neurosci Res. Volume: 91 Pages: 63-68
  • DOI: 10.1016/j.neures.2014.09.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Multiple system involvement in a Japanese patient with a V31A mutation in the SOD1 gene. (2014)
  • Author(s): 8.Sakamoto H, Akamatsu M, Hirano M, Saigoh K, Ueno S, Isono C, Kusunoki S, Nakamura Y.
  • Journal Title: Amyotroph Lateral Scler Frontotemporal Degener Volume: 15 Issue: 3-4 Pages: 312-314
  • DOI: 10.3109/21678421.2013.873051
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Overlapping demyelinating syndromes and anti-NMDA receptor encephalitis (2014)
  • Author(s): Titulaer MJ, Hoeftberger R, Iizuka T, Leypoldt F, McCracken L, Cellucci T, Benson LA, Shu H, Irioka T, Hirano M, Singh G, Calvo AC, Kaida K, Morales PS, Wirtz PW, Yamamoto T, Reindl M, Rosenfeld MR, Graus F, Saiz A, Dalmau J.
  • Journal Title: Ann Neurol Volume: 未定 Issue: 3 Pages: 411-428
  • DOI: 10.1002/ana.24117
  • Peer Reviewed
• [Journal Article] Multiple system involvement in a Japanese patient with a V31A mutation in the SOD1 gene (2014)
  • Author(s): Sakamoto H, Akamatsu M, Hirano M, Saigoh K, Ueno S, Isono C, Kusunoki S, Nakamura Y
  • Journal Title: Amyotroph Lateral Scler Frontotemporal Degener Volume: 未定
  • Peer Reviewed
• [Journal Article] Clinical features in Guillain-Barré syndrome with anti-Gal-C antibody. (2014)
  • Author(s): Samukawa M, Hamada Y, Kuwahara M, Takada K, Hirano M, Mitsui Y, Sonoo M, Kusunoki S, the Japanese GBS Study Group.
  • Journal Title: J Neurol Sci Volume: 337 Issue: 1-2 Pages: 55-60
  • DOI: 10.1016/j.jns.2013.11.016
  • Peer Reviewed
• [Journal Article] Differences in dysphagia between spinocerebellar ataxia type 3 and type 6 (2013)
  • Author(s): Isono C, Hirano M, Sakamoto H, Ueno S, Kusunoki S, Nakamura Y
  • Journal Title: Dysphagia Volume: 28 Issue: 3 Pages: 413-418
  • DOI: 10.1007/s00455-013-9450-4
  • Peer Reviewed
• [Journal Article] A case of severe ganciclovir-induced encephalopathy. (2013)
  • Author(s): Sakamoto H, Hirano M, Nose K, Ueno S, Oki T, Sugimoto K, Nishioka T, Kusunoki S, Nakamura Y
  • Journal Title: Case Rep Neurol Volume: 5 Issue: 3 Pages: 183-186
  • DOI: 10.1159/000355638
  • Peer Reviewed
• [Journal Article] Ophthalmologic involvement in Japanese siblings with chorea-acanthocytosis caused by a novel chorein mutation. (2013)
  • Author(s): Ogawa I, Saigoh K, Hirano M, Mtsui Y, Sugioka K, Takahashi J, Shimomura Y, Tani Y, Nakamura Y, Kusunoki S.
  • Journal Title: Parkinsonism Relat Disord Volume: 19 Issue: 10 Pages: 913-915
  • DOI: 10.1016/j.parkreldis.2013.05.012
  • Peer Reviewed
• [Presentation] 孤発性筋萎縮性側索硬化症の遺伝子解析による新規変異同定とカウンセリングの問題点 (2015)
  • Author(s): 平野牧人、中村雄作、西郷和真、阪本 光、上野周一、鈴木秀和、楠 進
  • Organizer: 人類遺伝学会
  • Place of Presentation: 京王プラザホテル (東京)
  • Year and Date: 2015-10-14
• [Presentation] Analyses of the VCP gene in Japanese patients with sporadic amyotrophic lateral sclerosis identify the novel mutation that increases susceptibility to oxidative stress (2015)
  • Author(s): Makito Hirano, MD, PhD1, 2, Yusaku Nakamura, Kazumasa Saigoh, Hikaru Sakamoto, Shuichi Ueno, Chiharu Isono, Susumu Kusunoki
  • Organizer: The Annual Meeting of American Neurological Association
  • Place of Presentation: Chicago (米国)
  • Year and Date: 2015-09-27
  • Int'l Joint Research
• [Presentation] Improvement of swallowing functions by rotigotine transdermal patch in patients with Parkinson’s disease (2015)
  • Author(s): Chiharu Isono, Makito Hirano, Hikaru Sakamoto, Shuichi Ueno, Susumu Kusunoki, Yusaku Nakamura
  • Organizer: The Annual Meeting of American Neurological Association
  • Place of Presentation: Chicago (米国)
  • Year and Date: 2015-09-27
  • Int'l Joint Research
• [Presentation] Analysis of sporadic amyotrophic lateral sclerosis detects a novel VCP mutation (2015)
  • Author(s): Makito Hirano, Yusaku Nakamura, Kazumasa Saigoh, Hikaru Sakamoto, Shuichi Ueno, MD, Susumu Kusunoki
  • Organizer: 神経学会総会
  • Place of Presentation: 朱鷺メッセ (新潟市)
  • Year and Date: 2015-05-20
• [Presentation] Rotigotine transdermal patchにより嚥下機能が著明に改善した誤嚥性肺炎合併パーキンソン病患者の一例 (2014)
  • Author(s): 平野牧人、磯野千春、上野周一、阪本 光、楠 進、中村雄作
  • Organizer: 日本神経治療学会
  • Place of Presentation: 東京(東京ドームホテル)
  • Year and Date: 2014-11-20 – 2014-11-22
• [Presentation] Analyses of the COQ2 gene in Japanese patients with multiple system atrophy and other neurodegenerative diseases (2014)
  • Author(s): Makito Hirano, Yusaku Nakamura, Kazumasa Saigoh, Hikaru Sakamoto, Shuichi Ueno, Yoshiyuki Mitsui, Susumu Kusunoki
  • Organizer: Annual Meeting of American Neurological Association
  • Place of Presentation: Baltimore
  • Year and Date: 2014-10-12 – 2014-10-14
• [Presentation] Differential progression of dysphagia between spinocerebeller ataxia type 3 and type 6 (2014)
  • Author(s): Chiharu Isono, Makito Hirano, Hikaru Sakamoto, Shuichi Ueno, Susumu Kusunoki, Yusaku Nakamura
  • Organizer: Annual Meeting of American Neurological Association
  • Place of Presentation: Baltimore
  • Year and Date: 2014-10-12 – 2014-10-14
• [Presentation] 多系統萎縮症および常染色体優性遺伝性脊髄小脳変性症におけるCOQ2遺伝子解析 COQ2 gene analyses in multiple system atrophy and dominantly-inherited ataxia (2014)
  • Author(s): 平野牧人、中村雄作、阪本 光、上野周一、三井良之、西郷和真、楠 進
  • Organizer: 日本神経学会総会
  • Place of Presentation: 福岡(福岡国際会議場)
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] 多系統の障害をきたしたSOD1変異例 (2014)
  • Author(s): 阪本 光、平野牧人、上野周一、赤松舞子、中村雄作、楠 進
  • Organizer: 日本神経学会総会
  • Place of Presentation: 福岡(福岡国際会議場)
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] Novel mutations in the SQSTM1 gene encoding p62 in Japanese patients with sporadic amyotrophic lateral sclerosis (2013)
  • Author(s): Makito Hirano, Yusaku Nakamura, Kazumasa Saigoh, Hikaru Sakamoto, Shuichi Ueno, Chiharu Isono, Susumu Kusunoki
  • Organizer: The Annual Meeting of American Neurological Association
  • Place of Presentation: ニューオリンズ
• [Presentation] p62/SQSTM1/遺伝子変異を有する筋萎縮性側索硬化症の線維芽細胞とiPS細胞の解析 (2013)
  • Author(s): 平野牧人、中村雄作、寺村岳士、 江良択実、西郷和真、阪本 光、上野周一、福田寛二、楠 進
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 仙台
• [Presentation] 孤発性筋萎縮性側索硬化症におけるC9ORF72, UBQLN2, PFN1, p62/SQSTM1遺伝子解析 (2013)
  • Author(s): 平野牧人、中村雄作、阪本 光、上野周一、西郷和真、楠 進
  • Organizer: 日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 孤発性筋萎縮性側索硬化症におけるp62/SQSTM1遺伝子の解析 (2013)
  • Author(s): 平野牧人、中村雄作、阪本 光、上野周一、西郷和真、楠 進
  • Organizer: Neuro2013
  • Place of Presentation: 京都
• [Book] Bardet-Biedl(バルデー・ビードル)症候群(pp495-497) 神経症候群IV (2014)
  • Author(s): 平野牧人
  • Total Pages: 835
  • Publisher: 日本臨床社
• [Book] 医学大辞典 (2014)
  • Author(s): 平野牧人、楠 進
  • Publisher: 南山堂