| Project/Area Number |
16H05219
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
矢吹 悌 東北大学, 薬学研究科, 助教 (70756121)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
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| 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 / FABP3 / 神経薬理学 / α－シヌクレイン / シヌクレイノパチー / 薬理学 / 脳神経疾患 / 脳・神経 / 薬物治療学 |
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| 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.
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| 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。
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