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Liman, J., Deeg, S., Voigt, A., Voßfeldt, H., Dohm, C.P., Karch, A., Weishaupt, J., Schulz, J.B., Bähr, M., Kermer, P. (2014). CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration.  J. Neurochem. 129(6): 1013--1023.
FlyBase ID
FBrf0225360
Publication Type
Research paper
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.

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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    J. Neurochem.
    Title
    Journal of Neurochemistry
    Publication Year
    1956-
    ISBN/ISSN
    0022-3042
    Data From Reference
    Alleles (6)
    Genes (4)
    Human Disease Models (2)
    Insertions (1)
    Transgenic Constructs (5)