Insoluble cellular aggregates are associated with a number of neurodegenerative disorders such as Alzheimer and Parkinson disease as well as diseases caused by expansion of a polyglutamine tract, such as Huntington disease and the spinocerebellar ataxias. How do polyglutamine-containing proteins cause neurodegeneration? The mutant forms of these proteins tend to aggregate in ubiquitin-positive inclusions in the nucleus. On page 148, Christopher Cummings and colleagues now report that ataxin-1 aggregates also stain positive for proteasome components and the HDJ-2/HSDJ chaperones. These findings raise the possibility that the cell may actively attempt to degrade the polyglutamine-containing ataxin-1 but is unable to finish the job. Keeping the cellular waste-removal machinery tied up in this futile attempt might limit the degradation and removal of other proteins — and ultimately contribute to cellular degeneration. Cummings et al. go on to show that overexpression of the HDJ-2/HSDJ chaperone in HeLa cells expressing mutant ataxin-1 decreases the frequency of aggregate formation. While it is too early to conclude that limited chaperone capacity is involved in disease pathology, the cell-line data raise the possibility that increased levels of available chaperone molecules directly suppress aggregate formation through refolding or removal of misfolded polyglutamine proteins. As the authors discuss, the next step will be to test whether similar results can be obtained in the intact animal.
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