| First Author | Takahashi H | Year | 2015 |
| Journal | Hum Mol Genet | Volume | 24 |
| Issue | 2 | Pages | 525-39 |
| PubMed ID | 25217572 | Mgi Jnum | J:217201 |
| Mgi Id | MGI:5613305 | Doi | 10.1093/hmg/ddu472 |
| Citation | Takahashi H, et al. (2015) Identification and characterization of PKCgamma, a kinase associated with SCA14, as an amyloidogenic protein. Hum Mol Genet 24(2):525-39 |
| abstractText | Amyloid assemblies are associated with a wide range of human disorders, including Alzheimer's and Parkinson's diseases. Here, we identify protein kinase C (PKC) gamma, a serine/threonine kinase mutated in the neurodegenerative disease spinocerebellar ataxia type 14 (SCA14), as a novel amyloidogenic protein with no previously characterized amyloid-prone domains. We found that overexpression of PKCgamma in cultured cells, as well as in vitro incubation of PKCgamma without heat or chemical denaturants, causes amyloid-like fibril formation of this protein. We also observed that SCA14-associated mutations in PKCgamma accelerate the amyloid-like fibril formation both in cultured cells and in vitro. We show that the C1A and kinase domains of PKCgamma are involved in its soluble dimer and aggregate formation and that SCA14-associated mutations in the C1 domain cause its misfolding and aggregation. Furthermore, long-term time-lapse imaging indicates that aggregates of mutant PKCgamma are highly toxic to neuronal cells. Based on these findings, we propose that PKCgamma could form amyloid-like fibrils in physiological and/or pathophysiological conditions such as SCA14. More generally, our results provide novel insights into the mechanism of amyloid-like fibril formation by multi-domain proteins. |
