Developmental drug study targeting PARK7/DJ-1, a causetive gene of familial Parkinson's disease
| Project/Area Number |
18K06904
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 48030:Pharmacology-related
|
|---|
| Research Institution | Ritsumeikan University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
肱岡 雅宣 名古屋市立大学, 医薬学総合研究院(医学), 助教 (50780061)
|
|---|
| Project Period (FY) |
2018-04-01 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | PARK7 / DJ-1 / DJ-1結合化合物 / α-シヌクレイン / ミクログリア / 神経細胞 / αシヌクレイン / PARK7/DJ-1 / 神経保護作用 / パーキンソン病 / アルツハイマー病 |
|---|
| Outline of Final Research Achievements |
DJ-1 protein is a normal gene product of familial Parkinson's disease PARK7. DJ-1-knocked down human SH-SY5Y cells markedly generated oxidative stress and then neural cell death. On the other hand, α-synuclein (α-syn) protein is known to accumulate the aggregated form in the brains of patients with synucleinopathies such as Parkinson's disease (PD). In this study, I establish the α-syn-aggregation system in SH-SY5Y cells and the evaluation system of microglial α-syn-phagocytosis. In addition, the exogenic treatment of preformed fibrils (PFFs) induced intracellular α-syn-aggregation in SH-SY5Y cells overexpressing the human SNCA gene. These results suggest that exogenous PFFs induced intracellular aggregation of α-syn protein harboring β-sheet structures from endogenous α-syn similar to prion-like spreading.
|
| Academic Significance and Societal Importance of the Research Achievements |
PARK7/DJ-1は家族性パーキンソン病の原因遺伝子として同定されたため、当初はパーキンソン病の治療薬としての創製を試みていた。しかし、強い抗酸化ストレス能をもつことから、他の神経変性疾患に対する治療標的の候補になると考えられた。そこで、プリオンと同様にα-シヌクレインが細胞内で凝集する細胞評価系を確立した。さらに、DJ-1の抗酸化能調節部位であるC106残基に結合する化合物を見出し、その化合物に神経細胞保護効果があることを明らかにした。本研究課題で得られた研究成果により、パーキンソン病だけでなく、他の神経変性疾患にも効く新たなシード薬を見出し、社会的意義がある。
|
Report
(4 results)
Research Products
(22 results)
-
[Journal Article] Mouse Bone Marrow-derived Microglia-like Cells Secrete Transforming Growth Factor-β1 and Promote Microglial Aβ Phagocytosis and Reduction of Brain Aβ2020
Author(s)
Kuroda E, Nishimura K, Kawanishi S, Sueyoshi M, Ueno F, Toji Y, Abo N, Konishi T, Harada K, Satake S, Shima C, Toda Y, Kitamura Y, Shimohama S, Ashihara E, Takata K.
-
Journal Title
Neuroscience
Volume: 438
Pages: 217-228
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
[Journal Article] Peripheral blood-derived microglia-like cells decrease amyloid-β burden and ameliorate cognitive impairment in a mouse model of Alzheimer’s disease.2020
Author(s)
Kuroda E., Takata K., Nishimura K., Oka H., Sueyoshi M., Aitani M., Kouda A., Satake S., Shima C., Toda Y., Nakata S., Kitamura Y., and Ashihara E.
-
Journal Title
J. Alzheimers Dis.
Volume: 73 (1)
Issue: 1
Pages: 413-429
DOI
Related Report
Peer Reviewed
-
[Journal Article] Bone-marrow-derived microglia-like cells ameliorate brain amyloid pathology and cognitive impairment in a mouse model of Alzheimer's disease.2018
Author(s)
Kawanishi S., Takata K., Itezono S., Nagayama H., Konoya S., Chisaki Y., Toda Y., Nakata S., Yano Y., Kitamura Y., Ashihara E.
-
Journal Title
J. Alzheimer’s Dis.
Volume: 64
Issue: 2
Pages: 563-585
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
-
-
-
-
-
-
-
-
-
-
-
[Book] 認知症plus予防教育2020
Author(s)
肱岡雅宣, 天ヶ瀬紀久子, 北村佳久.
Total Pages
216
Publisher
日本看護協会出版会
ISBN
9784818022485
Related Report
-
-
-
