Drug development by investigation of a-synucelin aggregation mechanism through FABP
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 |
Section | 一般 |
Research Field |
Applied pharmacology
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Research Institution | Tohoku University |
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 |
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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Report
(4 results)
Research Products
(89 results)
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[Journal Article] Reduced CaM kinase II and CaM Kinase IV activities underlie cognitive deficits in NCKX2 heterozygous mice2018
Author(s)
Moriguchi S, Kita S, Yabuki Y, Inagaki R, Izumi H, Sasaki Y, Tagashira H, Horie K, Takeda J, Iwamoto T, Fukunaga K
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Journal Title
Mol Neurobiol
Volume: 55
Pages: 3889-3900
DOI
Related Report
Peer Reviewed
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[Journal Article] Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy2018
Author(s)
Moriguchi S, Ishizuka T, Yabuki Y, Shioda N, Sasaki Y, Tagashira H, Yawo H, Yeh JZ, Sakagami H, Narahashi T, Fukunaga K
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Journal Title
Mol Psychiatry
Volume: 23
Pages: 211-221
DOI
Related Report
Peer Reviewed
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[Journal Article] Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer2017
Author(s)
Yabuki Y, Matsuo K, Izumi H, Haga H, Yoshida T, Wakamori M, Kakei A, Sakimura K, Fukuda T, Fukunaga K
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Journal Title
Neuropharmacology
Volume: 117
Pages: 1-13
DOI
Related Report
Peer Reviewed
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[Journal Article] Trans-fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway.2017
Author(s)
Hirata Y, Takahashi M, Kudoh Y, Kano K, Kawana H, Makide K, Shinoda Y, Yabuki Y, Fukunaga K, Aoki J, Noguchi T, Matsuzawa A
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Journal Title
J Biol Chem
Volume: -
Pages: -
DOI
Related Report
Peer Reviewed
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[Journal Article] Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer.2017
Author(s)
Yabuki Y, Matsuo K, Izumi H, Haga H, Yoshida T, Wakamori M, Kakei A, Sakimura K, Fukuda T, Fukunaga K.
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Journal Title
Neuropharmacology.
Volume: 117
Pages: 1-13
DOI
Related Report
Peer Reviewed
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[Journal Article] Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy.2016
Author(s)
Moriguchi S, Ishizuka T, Yabuki Y, Shioda N, Sasaki Y, Tagashira H, Yawo H, Yeh JZ, Sakagami H, Narahashi T, Fukunaga K.
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Journal Title
Mol Psychiatry.
Volume: -
Pages: -
DOI
Related Report
Peer Reviewed
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[Journal Article] Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia.2016
Author(s)
Wang XJ, Gao YP, Lu NN, Li WS, Xu JF, Ying XY, Wu G, Liao MH, Tan C, Shao LX, Lu YM, Zhang C, Fukunaga K, Han F, Du YZ.
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Journal Title
ACS Appl Mater Interfaces.
Volume: 8
Pages: 35045-35058
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism.2016
Author(s)
Huang JY, Tian Y, Wang HJ, Shen H, Wang H, Long S, Liao MH, Liu ZR, Wang ZM, Li D, Tao RR, Cui TT, Moriguchi S, Fukunaga K, Han F, Lu YM.
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Journal Title
CNS Neurosci Ther.
Volume: 22
Pages: 845-853
DOI
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Peer Reviewed / Int'l Joint Research
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[Journal Article] Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia.2016
Author(s)
Wang R, Wang ST, Wang YD, Wu G, Du Y, Qian MQ, Liang XG, Elbatreek MH, Yang HY, Liu ZR, Fukunaga K, Liu JX, Lu YM.
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Journal Title
Neuroreport.
Volume: 27
Pages: 445-454
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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