Clarification of the pathogenesis of multiple system atrophy and its treatment strategy using AMBRA1

• Project/Area Number: 16K19503
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Hirosaki University
• Principal Investigator: MIKI YASUO 弘前大学, 医学研究科, 助教 (30709142)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: AMBRA1 / オートファジー / 多系統萎縮症 / シヌクレイノパチー / αシヌクレイン

Outline of Final Research Achievements

The accumulation of abnormal α-synuclein is the histopathological feature of multiple system atrophy (MSA). Autophagy is regulated by various proteins including autophagy/beclin1 regulator 1 (AMBRA1). We conducted the present study to elucidate the role of AMBRA1 in the pathogenesis of MSA.
Pathological and biochemical analyses using human brain samples revealed that AMBRA1 is a component of the pathological hallmarks of MSA. A 9-fold stronger affinity was found in AMBRA1 with abnormal α-synuclein compared with non-phosphorylated α-synuclein. Significant correlation between AMBRA1 overexpression and reduction of abnormal α-synuclein was observed. AMBRA1 overexpression or knockdown significantly changed α-synuclein in the mammalian cells.
Our results demonstrated that molecular modulation targeting AMBRA1 can be a promising candidate for the treatment of MSA.

Research Products

• [Int'l Joint Research] Universita del Salento(イタリア)
• [Journal Article] Immunohistochemical localization of exoribonucleases (DIS3L2 and XRN1) in intranuclear inclusion body disease (2018)
  • Author(s): Mori Fumiaki、Tanji Kunikazu、Miki Yasuo、Toyoshima Yasuko、Sasaki Hidenao、Yoshida Mari、Kakita Akiyoshi、Takahashi Hitoshi、Wakabayashi Koichi
  • Journal Title: Neuroscience letters Volume: 662 Pages: 389-394
  • DOI: 10.1016/j.neulet.2017.10.061
  • Peer Reviewed
• [Journal Article] Alteration of autophagy-related proteins in peripheral blood mononuclear cells of patients with Parkinson's disease (2018)
  • Author(s): Miki Yasuo、Shimoyama Shuji、Kon Tomoya、Ueno Tatsuya、Hayakari Ryo、Tanji Kunikazu、Matsumiya Tomoh、Tsushima Eiki、Mori Fumiaki、Wakabayashi Koichi、Tomiyama Masahiko
  • Journal Title: Neurobiology of aging Volume: 63 Pages: 33-43
  • DOI: 10.1016/j.neurobiolaging.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] YOD1 attenuates neurogenic proteotoxicity through its deubiquitinating activity (2018)
  • Author(s): Tanji Kunikazu、Mori Fumiaki、Miki Yasuo、Utsumi Jun、Sasaki Hidenao、Kakita Akiyoshi、Takahashi Hitoshi、Wakabayashi Koichi
  • Journal Title: Neurobiology of disease Volume: 112 Pages: 14-23
  • DOI: 10.1016/j.nbd.2018.01.006
  • Peer Reviewed
• [Journal Article] Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. (2017)
  • Author(s): Miki Y, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Biochem Biophys Res Commun Volume: 489 Issue: 4 Pages: 439-444
  • DOI: 10.1016/j.bbrc.2017.05.162
  • Peer Reviewed
• [Journal Article] Status epilepticus causing extensive microvacuolar change with astrocytosis and diffusion MRI abnormalities in the subcortical white matter (2017)
  • Author(s): Miki Yasuo、Tanji Kunikazu、Kimura Kensuke、Yajima Nobuhisa、Mori Fumiaki、Wakabayashi Koichi
  • Journal Title: Journal of the neurological sciences Volume: 382 Pages: 55-57
  • DOI: 10.1016/j.jns.2017.09.029
  • Peer Reviewed
• [Journal Article] AMBRA1, a novel alpha-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy. (2017)
  • Author(s): Miki Y, Tanji K, Mori F, Tatara Y, Utsumi J, Sasaki H, Kakita A, Takahashi H, Fimia GM, Wakabayashi K.
  • Journal Title: Brain Pathol Volume: 印刷中 Issue: 1 Pages: 28-42
  • DOI: 10.1111/bpa.12461
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neuropathology of PARK14 is identical to idiopathic Parkinson's disease (2017)
  • Author(s): Miki Y, Yoshizawa T, Morohashi S, Seino Y, Kijima H, Shoji M, Mori A, Yamashita C, Hatano T, Hattori N, Wakabayashi K
  • Journal Title: Mov Disord Volume: - Issue: 5 Pages: 35-35
  • DOI: 10.1002/mds.26952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PLA2G6 accumulates in Lewy bodies in PARK14 and idiopathic Parkinson's disease. (2017)
  • Author(s): Miki Y, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 645 Pages: 40-45
  • DOI: 10.1016/j.neulet.2017.02.027
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] PARK14の1剖検例 (2017)
  • Author(s): 三木康生、吉澤忠司、諸橋聡子、清野祐輔、鬼島宏、東海林幹夫、森聡生、山下力、波田野琢、服部信孝、若林孝一
  • Organizer: 第58回日本神経病理学会総会学術研究会
• [Presentation] PLA2G6はPARK14と特発性パーキンソン病のレヴィ小体に蓄積する (2017)
  • Author(s): 三木康生、丹治邦和、森文秋、柿田明美、高橋均、若林孝一
  • Organizer: 第58回日本神経病理学会総会学術研究会
• [Presentation] シヌクレイノパチーにおけるオートファジーの異常とその活性化による治療の可能性 (2017)
  • Author(s): 三木康生
  • Organizer: 第36回日本認知症学会学術集会
  • Invited
• [Presentation] 多系統萎縮症におけるオートファジー上流分子の異常 (2016)
  • Author(s): 三木康生、丹治邦和、森文秋、内海潤、佐々木秀直、柿田明美、高橋均、若林孝一
  • Organizer: 第57回日本神経病理学会総会学術研究会
  • Place of Presentation: ホテルニューキャッスル（青森県弘前市）
  • Year and Date: 2016-06-01
• [Presentation] PARK14の１剖検例 (2016)
  • Author(s): 三木康生、吉澤忠司、諸橋聡子、清野祐輔、田中正則、鬼島宏、若林孝一
  • Organizer: 第23回東北神経病理研究会
  • Place of Presentation: 山形大学（山形県山形市）