CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration
Article first published online: 24 MAR 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 129, Issue 6, pages 1013–1023, June 2014
How to Cite
J. Neurochem. (2014) 129, 1013–1023.
- Issue published online: 11 JUN 2014
- Article first published online: 24 MAR 2014
- Accepted manuscript online: 18 FEB 2014 12:24PM EST
- Manuscript Accepted: 3 FEB 2014
- Manuscript Revised: 27 DEC 2013
- Manuscript Received: 2 SEP 2013
- National Ataxia Foundation
- KNDD. Grant Number: 01GI0703
- SCA3, neurodegeneration
Spinocerebellar ataxia type 3 (SCA3) is one of at least nine inherited neurodegenerative diseases caused by an expansion of a polyglutamine tract within corresponding disease-specific proteins. In case of SCA3, mutation of Ataxin-3 results in aggregation of misfolded protein, formation of intranuclear as well as cytosolic inclusion bodies and cell death in distinct neuronal populations. Since cyclin-dependent kinase-5 (CDK5) has been shown to exert beneficial effects on aggregate formation and cell death in various polyglutamine diseases, we tested its therapeutic potential for SCA3. Our data show increased caspase-dependent Ataxin-3 cleavage, aggregation, and neurodegeneration in the absence of sufficient CDK5 activity. This disease-propagating effect could be reversed by mutation of the caspase cleavage site in Ataxin-3. Moreover, reduction of CDK5 expression levels by RNAi in vivo enhances SCA3 toxicity as assayed in a Drosophila model for SCA3. In summary, we present CDK5 as a potent neuroprotectant, regulating cleavage and thereby toxicity of Ataxin-3 and other polyglutamine proteins.
We propose that increased caspase-dependent cleavage of mutated Ataxin-3, because of missing CDK5 shielding, leads to aggregation and cell death. Moreover, reduction of CDK5 expression levels by RNAi in vivo enhances SCA3 toxicity as assayed in a Drosophila model for SCA3. We think that CDK5 functions as a shield against cleavage-induced toxification and thereby is an interesting target for therapeutic intervention in polyQ disease in general.