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Cdk5 protects huntingtin

Cdk5 (red) phosphorylates htt (green) and protects it from caspases.

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 neurons.

In contrast to full-length htt, mutant fragments interfered with cdk5's protection. In brains of a mouse HD model, cdk5 activity was reduced. This inactivity arises because the mutant fragments interfere with the interaction of cdk5 and its activator, p35. Thus, as more fragments accumulate, less full-length htt is protected from cleavage. This positive feedback might explain the rapid neurodegeneration that occurs after HD onset. It is not yet clear what levels of mutant htt fragments are required to reduce the activity of cdk5 such that cleavage is promoted and the positive feedback loop initiated.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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Related Article

Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity

Shouqing Luo, Coralie Vacher, Janet E. Davies, and David C. Rubinsztein
J. Cell Biol. 2005 169: 647-656. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 814K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                            What's this?