| First Author | Parmasad JA | Year | 2024 |
| Journal | Cell Death Dis | Volume | 15 |
| Issue | 4 | Pages | 246 |
| PubMed ID | 38575601 | Mgi Jnum | J:352906 |
| Mgi Id | MGI:7619214 | Doi | 10.1038/s41419-024-06534-8 |
| Citation | Parmasad JA, et al. (2024) Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy. Cell Death Dis 15(4):246 |
| abstractText | Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of alpha-Synuclein (alpha-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the alpha-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress alpha-Syn replicate several features of PD. Decreasing total alpha-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of alpha-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of alpha-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the alpha-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical alpha-Syn pathology, indicated by reduced numbers of pS129 alpha-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic alpha-Syn species. We further validated these findings on pS129 alpha-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated alpha-Syn in human neurons, in PFF-challenged rat neurons and in the brains of alpha-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy. |
