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.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Liman J,Deeg S,Voigt A,Voßfeldt H,Dohm CP,Karch A,Weishaupt J,Schulz JB,Bähr M,Kermer Pdoi
10.1111/jnc.12684subject
Has Abstractpub_date
2014-06-01 00:00:00pages
1013-23issue
6eissn
0022-3042issn
1471-4159journal_volume
129pub_type
杂志文章abstract：:Some data on the concentration range of response and the concentration for half-response (EC50) of gamma-aminobutyric acid (GABA) for the GABAA receptor are reviewed and compared. An analysis of the 36Cl- flux assay demonstrates that both the EC50 and the slope of a Hill plot depend on the ion influx or efflux assay t...
journal_title：Journal of neurochemistry
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pub_type： 杂志文章
doi：10.1111/j.1471-4159.1992.tb09374.x
更新日期：1992-03-01 00:00:00
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journal_title：Journal of neurochemistry
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