Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease

Parkinsona’s disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene ( SNCA ) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-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 α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-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 α-Syn in human neurons, in PFF- challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy. ### Competing Interest Statement The authors have declared no competing interest. * α-Syn : α-Synuclein BDW : bodyweight CDK14 : cyclin-dependent kinase 14 CL : contralateral CTT : C-terminally truncated α-Syn DAB : diaminobenzidine DaNs : dopaminergic neurons DIV : days in vitro ELISA : enzyme-linked immunosorbent essay H&E : hematoxylin and eosin hESC : human embryonic stem cell high exp. : high exposure hiPSC : human induced pluripotent stem cell IL : ipsilateral min : minutes KO : knockout LC-MS/MS : liquid chromatography – mass spectrometry/mass spectrometry Mono : α-Synuclein monomers NPC : neural precursor cell PBS : phosphate-buffered saline PD : Parkinson’s disease PFFs : α-Synuclein preformed fibrils RT : room temperature sec : seconds SEM : standard error of the mean SN : substantia nigra pars compacta TG : transgene UT : untreated WT : Wildtype