title: CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration.
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.
authors.affiliation: Department of Neurology, University of Göttingen, Göttingen, Germany; Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Goettingen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Liman
authors.forename: Sebastian
authors.initials: S
authors.lastname: Deeg
authors.forename: Aaron
authors.initials: A
authors.lastname: Voigt
authors.forename: Hannes
authors.initials: H
authors.lastname: Voßfeldt
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Dohm
authors.forename: André
authors.initials: A
authors.lastname: Karch
authors.forename: Jochen
authors.initials: J
authors.lastname: Weishaupt
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Pawel
authors.initials: P
authors.lastname: Kermer
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003720:Densitometry; D004330:Drosophila; D005455:Fluorescent Antibody Technique; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D007150:Immunohistochemistry; D017827:Machado-Joseph Disease / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids; D012097:Repressor Proteins / Q000378:metabolism*; D016019:Survival Analysis; D014162:Transfection
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D051360:Cyclin-Dependent Kinase 5; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D020169:Caspases
keywords: Ataxin-3; CDK5; SCA3, neurodegeneration; caspase