CDK5 protects from caspase‐induced Ataxin‐3 cleavage and neurodegeneration. (24th March 2014)

• Record Type: Journal Article
• Authors: Liman, Jan; Deeg, Sebastian; Voigt, Aaron; Voßfeldt, Hannes; Dohm, Christoph P.; Karch, André; Weishaupt, Jochen; Schulz, Jörg B.; Bähr, Mathias; Kermer, Pawel
• Is Part Of: Journal of neurochemistry. Volume 129:Number 6(2014:Jun.)
• Page Start: 1013
• Page End: 1023
• Publication Date: 2014-03-24
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12684
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12684-abs-0001"> <title>Abstract</title> <p>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 <italic>in vivo</italic> enhances SCA3 toxicity as assayed in a <italic>Drosophila</italic> model for SCA3. In summary, we present CDK5 as a potent neuroprotectant, regulating cleavage and thereby toxicity of Ataxin‐3 and other polyglutamine proteins.</p> <p> <boxed-text content-type="graphic" id="jnc12684-blkfxd-1001" position="anchor" orientation="portrait"> <graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pghmh3qbsk" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> </boxed-text> </p> <p>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 <italic>in vivo</italic> enhances SCA3 toxicity as assayed in a <italic>Drosophila</italic> 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.</p> </abstract>