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CDK 5 protects from caspase‐induced Ataxin‐3 cleavage and neurodegeneration
Author(s) -
Liman Jan,
Deeg Sebastian,
Voigt Aaron,
Voßfeldt Hannes,
Dohm Christoph P.,
Karch André,
Weishaupt Jochen,
Schulz Jörg B.,
Bähr Mathias,
Kermer Pawel
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12684
Subject(s) - neurodegeneration , microbiology and biotechnology , cleavage (geology) , chemistry , cyclin dependent kinase , caspase , neuroscience , nlrp1 , apoptosis , biology , biochemistry , cell cycle , programmed cell death , medicine , disease , paleontology , fracture (geology)
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 SCA 3, 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 ( CDK 5) has been shown to exert beneficial effects on aggregate formation and cell death in various polyglutamine diseases, we tested its therapeutic potential for SCA 3. Our data show increased caspase‐dependent Ataxin‐3 cleavage, aggregation, and neurodegeneration in the absence of sufficient CDK 5 activity. This disease‐propagating effect could be reversed by mutation of the caspase cleavage site in Ataxin‐3. Moreover, reduction of CDK 5 expression levels by RNA i in vivo enhances SCA 3 toxicity as assayed in a Drosophila model for SCA 3. In summary, we present CDK 5 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.