Expanded glutamines and neurodegeneration--a gain of insight

Glutamine repeat expansion has been established as the mutation underlying five inherited neurodegenerative diseases. The mechanism by which this apparently universal mutation, in ubiquitously expressed proteins, causes highly selective neurodegeneration is unknown. The proteins containing the glutamine expansions are otherwise unrelated and likely to have different functions. Two recently published papers provide evidence of a conformational change occurring in polyglutamine expansions, which may allow novel interactions and is consistent with a toxic gain-of-function hypothesis. HAP1, a protein that interacts with huntingtin (Huntington's disease protein), has an expression profile that intriguingly mirrors the selective neurodegeneration seen in Huntington's disease.