Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy

  • Cell Death Dis. 2024 Apr 4;15(4):246. doi: 10.1038/s41419-024-06534-8.
Jean-Louis A Parmasad  #  1  2 ,  Konrad M Ricke  #  1  2  3 ,  Benjamin Nguyen  1  2  3 ,  Morgan G Stykel  4 ,  Brodie Buchner-Duby  4 ,  Amanda Bruce  1  2 ,  Haley M Geertsma  1  2  3 ,  Eric Lian  2  5  6 ,  Nathalie A Lengacher  1  3  5 ,  Steve M Callaghan  1  2  3 ,  Alvin Joselin  7 ,  Julianna J Tomlinson  1  3  5 ,  Michael G Schlossmacher  1  3  5 ,  William L Stanford  2  5  6 ,  Jiyan Ma  8  9 ,  Patrik Brundin  8 ,  Scott D Ryan  4 ,  Maxime W C Rousseaux  10  11  12  13
Affiliations
  • 1. University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
  • 2. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
  • 3. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • 4. Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
  • 5. Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
  • 6. Ottawa Institute for Systems Biology, University of Ottawa, Ottawa, ON, Canada.
  • 7. Hotchkiss Brain Institute, Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.
  • 8. Parkinson's Disease Center, Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
  • 9. Chinese Institute for Brain Research, Beijing, China.
  • 10. University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada. [email protected].
  • 11. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada. [email protected].
  • 12. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [email protected].
  • 13. Ottawa Institute for Systems Biology, University of Ottawa, Ottawa, ON, Canada. [email protected].
  • # Contributed equally.
PMID: 38575601 DOI: 10.1038/s41419-024-06534-8
Abstract

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.