1. Department of Neurology, University of G?ttingen, , G?ttingen, Germany;2. Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), , Goettingen, Germany;3. Department of Neurology, University Medical Center, RWTH Aachen, , Aachen, Germany;4. NCU, University Ulm, , Ulm, Germany;5. Department of Neurology, Nordwest‐Krankenhaus Sanderbusch GmbH, , Sande, Germany
Abstract:
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.
