2017 Fiscal Year Final Research Report
Investigation of Parkinsonism by PKC pathway disruption and application for the new treatment for Parkinon's disease
| Project/Area Number |
16K19019
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
General pharmacology
|
|---|
| Research Institution | Hiroshima University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2016-04-01 – 2018-03-31
|
| Keywords | PKC / パーキンソン病 / リン酸化 / CSPalpha / HPS70 |
|---|
| Outline of Final Research Achievements |
We focused on cysteine string protein alpha (CSPa), one of HSP40 localized on synaptic vesicles. We found that PKCg phosphorylates CSPa at Serine10 and Ser34. Apoptosis was found to have been enhanced by the overexpression of a phosphorylation null mutant of CSPa, CSPa(S10A/S34A). The CSPa(S10A/S34A) mutant had a weaker interaction with HSP70 than WT CSPa, but a phosphomimetic CSPa(S10D/S34D) mutant had a stronger interaction with HSP70 than WT CSPa. Total levels of SNAP25, a main downstream of the HSP70 chaperone complex, was found to have decreased by the CSPa(S10A/S34A) mutant, through increased ubiquitination of SNAP25 in PC12 cells. In the striatum of 2-year-old PKCg KO mice, decreased phosphorylation levels of CSPa and decreased SNAP25 protein levels were observed. These findings indicate the phosphorylation of CSPa by PKCg may protect the presynaptic terminal from neurodegeneration. The PKCg-CSPa-HSP70-SNAP25 axis may provide a new therapeutic target for the treatment of PD.
|
| Free Research Field |
神経変性疾患
|
