Neurodegeneration: proper folding of polyQ proteins

Polyglutamine (polyQ) diseases, including Huntington’s disease, are characterized by the progressive neuronal degeneration that results from the misfolding and aggregation of proteins that contain expanded repeats of uninterrupted glutamines. There is no cure for polyQ diseases, but increasing the concentration of protein chaperones might prevent some of the protein misfolding, and stop or slow the disease process. Neef et al. performed a pharmacological screen in yeast to identify molecules that increase the production of heat shock transcription factor 1 (HSF1), which regulates levels of protein chaperones in the cell. They identified HSF1A as a chemical activator of human HSF1 in yeast, which leads to Hsp70 expression in rat neurons. HSF1A treatment also reduced the aggregation of polyQ proteins in a Drosophila model of polyQ toxicity. This suggests that HSF1A may alleviate some of the misfolding and aggregation of polyQ proteins that causes neurodegeneration.