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

2017 Fiscal Year Final Research Report

• 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
• 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.

Free Research Field

神経病理学