Journal Article

Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy

Ricke, Konrad M., Nguyen, Benjamin, Lengacher, Nathalie A., Rousseaux, Maxime W. C., Tomlinson, Julianna J., Ma, Jiyan, Buchner-Duby, Brodie, Stykel, Morgan G., Brundin, Patrik, Bruce, Amanda, Lian, Eric, Joselin, Alvin, Parmasad, Jean-Louis A., Ryan, Scott D., Callaghan, Steve M., Schlossmacher, Michael G., Stanford, William L., Geertsma, Haley M.

2024

Overview

Parkinson’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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/51 / 14/19 / 42/100 / 42/41 / 631/378/340 / 64/60 / 692/308/2778 / 692/699/375/1718 / 82/51 / alpha-Synuclein - genetics / alpha-Synuclein - metabolism / Animal models / Animals / Antibodies / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Culture / Cyclin-Dependent Kinases - genetics / Cyclin-Dependent Kinases - metabolism / Dopamine receptors / Dopaminergic Neurons - metabolism / Fibrils / Genetic screening / Humans / Immunology / Kinases / Life Sciences / Mesencephalon / Mesencephalon - metabolism / Mice / Movement disorders / Neurodegenerative diseases / Neurodegenerative Diseases - metabolism / Parkinson Disease - drug therapy / Parkinson Disease - genetics / Parkinson Disease - metabolism / Parkinson's disease / Rats / Synuclein / Synucleinopathies - metabolism / Synucleinopathies - pathology / Therapeutic targets