Cdk5 protects huntingtin

A cyclin-dependent kinase protects neurons from toxic fragments of huntingtin (htt), according to Luo et al. (page 647).Htt has various neurological functions, including vesicle trafficking. Htt is a common substrate for proteases that cleave the protein into smaller fragments, although the function of this cleavage is so far unknown. Mutant versions of htt with an expanded polyglutamine tract (>38 residues) form toxic aggregate-prone fragments that kill neurons and cause Huntington's disease (HD). The new findings show that the number of these fragments is minimized via the actions of cdk5.

The group found that cdk5 phosphorylates htt and thus protects it from cleavage by caspases. The protection might be due to the resulting charge change or a structural alteration that blocks protease accessibility. Phosphorylated, and thus uncleaved, mutant htt was much less toxic to...