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.