Drug development by investigation of a-synucelin aggregation mechanism through FABP

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05219
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Tohoku University
• Principal Investigator: Fukunaga Kohji 東北大学, 薬学研究科, 教授 (90136721)
• Co-Investigator(Kenkyū-buntansha): 矢吹 悌 東北大学, 薬学研究科, 助教 (70756121)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: パーキンソン病 / 脂肪酸結合蛋白質 / FABPリガンド / αシヌクレイン / アラキドン酸

Outline of Final Research Achievements

Fatty acid-binding protein 3 (FABP3) is highly expressed in the brain and accelerates α-synuclein (αSyn) oligomerization when cells are exposed to 1-Methyl-1,2,3,6-tetrahydropiridine (MPTP). Here, we demonstrate that αSyn oligomerization was markedly enhanced by FABP3 overexpression in neuro-2A cells when cells were stimulated with arachidonic acid. To inhibit the interaction between FABP3 and αSyn, we developed FABP3 ligands, which bind to the fatty acid-binding domain of FABP3. We finally succeeded development of FABP3-specific ligands derived from FABP4 ligand, BMS309403. The ligands 1, 7, and 8 significantly reduced arachidonic acid-induced αSyn oligomerization in neuro-2A cells. We also confirmed that ligand 1 improves motor dysfunction and cognition in MPTP-induced Parkinson’s model mice. Taken together, our results indicate that FABP3 ligands targeting FABP3 are useful as potential therapeutics that inhibits αSyn aggregation in Lewy Body diseases.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

2020年には我が国の認知症の患者数は600万人になり、そのうち300万人がアルツハイマー病、120万人がレビー小体型認知症である。特にレビー小体型認知症は患者のQOLが悪く、予後が悪い。根本的治療法がない中、認知症の超早期段階での診断、認知症進行の抑止（予防）薬開発が重要な課題となっている。本研究ではレビー小体型認知症の原因蛋白質であるαシヌクレインのオリゴマー形成に脳内脂肪酸結合蛋白質が関与することを明らかにした。さらに、脂肪酸結合蛋白質リガンドがαシヌクレインの凝集と毒性を抑制し、認知症進行を抑制する治療薬を開発した。本リガンドはレビー小体型認知症の疾患修飾治療薬として期待される。