Role of repeats in protein clearance

Abstract

Mutant proteins that contain stretches called polyQ repeats can misfold or form aggregates linked to neurodegeneration. It emerges that some polyQ-containing proteins regulate a process that degrades misfolded proteins. See Letter p.108 Expanded polyglutamine (polyQ) tracts in different proteins are a common feature of many neurodegenerative diseases. Many normal proteins also carry these tracts, although their function remains unclear. David Rubinsztein and colleagues show that polyQ tracts in a normal ataxin protein have a role in the degradative process of autophagy. In this case, the polyQ domain allows ataxin 3 interaction with the autophagy mediator beclin 1. Ataxin 3 can thus deubiquitinate beclin 1, preventing its degradation by the proteasome and allowing it to initiate autophagy. The team not only demonstrate the relevance of their findings to the process of autophagy in neurons, but also show how, under disease conditions, the polyQ tracts in mutant proteins compete with those in ataxin 3 to prevent beclin 1 stabilization and so impair starvation-induced autophagy.