Nine neurodegenerative diseases are driven by proteins that contain expanded polyglutamine (polyQ) tracts; these include huntingtin in Huntington’s disease and ataxin-3 in spinocerebellar ataxia type 3 (SCA3) where reduced age of disease onset is linked to increasing polyQ length. At the Cambridge Institute for Medical Research, the group of David Rubinsztein has now discovered that ataxin-3 normally regulates the cell’s recycling system, called autophagy. In healthy cells, autophagy is turned on during starvation to recycle cell components and so promote cell survival, but it is also important for removing protein aggregates such as those forming in neurodegeneration. In Nature, Rubinsztein and colleagues describe their findings that ataxin-3 controls this process by binding and protecting another factor called beclin-1 from proteasome-mediated degradation, thereby enabling autophagy.

They find that a problem arises when other disease proteins with expanded polyQ repeats are present, and start to compete with ataxin-3 for beclin-1 binding. This disrupts autophagy – both in the brain of a mouse model for Huntington’s disease, and in cells from patients – and also leads to reduced clearance of protein aggregates in cells. So this may indicate that this role for normal ataxin-3 in direct control of autophagy in healthy cells could also be a contributing factor to disease pathogenesis in late-onset neurodegenerative disease.