Abstract
The discovery of cell cycle regulators has directed cell research into uncharted territory. In dividing cells, cell cycle-associated protein kinases, which are referred to as cyclin-dependent-kinases (Cdks), regulate proliferation, differentiation, senescence and apoptosis. In contrast, all Cdks in post-mitotic neurons, with the notable exception of Cdk5, are silenced. Surprisingly, misregulation of Cdks occurs in neurons in a wide diversity of neurological disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Ectopic expression of these proteins in neurons potently induces cell death with hallmarks of apoptosis. Deregulation of the unique, cell cycle-unrelated Cdk5 by its truncated co-activator, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of non-membrane-associated proteins and possibly through the induction of cell cycle proteins. On the other hand, cycling Cdks such as Cdk2, Cdk4 and Cdk6, initiate death pathways by derepressing E2F-1/Rb-dependent transcription at the neuronal G1/S checkpoint. Thus, Cdk5 and cycling Cdks may have little in common in the healthy CNS, but they likely conspire in leading neurons to their demise.
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Abbreviations
- Cdks:
-
cyclin-dependent-kinases
- CKIs:
-
CDK-Inhibitory subunits
- AD:
-
Alzheimer's disease
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Acknowledgements
Due to lack of space, we were unable to cite all papers relevant to the topic. We apologize for this inconvenience. This work is supported by the Canadian Institutes of Health Research (CIHR) (to WE Mushynski and J-P Julien), the ALS Society of Canada, the Neuromuscular Funds, the National Institutes of Health (USA) and the Center for Research on ALS at Johns Hopkins University (to J-P Julien). MD Nguyen was a recipient of a KM Hunter-CIHR Ph.D. Scholarship and is currently supported by a Human Frontier Science Program Long-Term Fellowship. WE Mushynski is a CIHR Scientist. J-P Julien holds a CIHR Senior Investigator Award.
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Nguyen, M., Mushynski, W. & Julien, JP. Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ 9, 1294–1306 (2002). https://doi.org/10.1038/sj.cdd.4401108
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