CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration

J Neurochem. 2014 Jun;129(6):1013-23. doi: 10.1111/jnc.12684. Epub 2014 Mar 24.

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. 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.

Keywords: Ataxin-3; CDK5; SCA3, neurodegeneration; caspase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • Blotting, Western
  • Caspases / metabolism*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 5 / pharmacology*
  • Densitometry
  • Drosophila
  • Fluorescent Antibody Technique
  • Humans
  • Huntington Disease / genetics
  • Immunohistochemistry
  • Machado-Joseph Disease / genetics
  • Mutagenesis, Site-Directed
  • Nerve Degeneration / pathology
  • Nerve Degeneration / prevention & control*
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Plasmids
  • Repressor Proteins / metabolism*
  • Survival Analysis
  • Transfection

Substances

  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Cyclin-Dependent Kinase 5
  • ATXN3 protein, human
  • Ataxin-3
  • Caspases