Polyglutamine diseases, including Huntington's disease , designate a group of nine neurodegenerative disorders characterized by the presence of a toxic polyglu-tamine expansion in specific target proteins. Using cell and mouse models, we have shown that expanded poly-glutamine led to activation of the stress kinase JNK and the transcription factor AP-1, which are implicated in neuronal death. Polyglutamine expansion-induced stress shared common features with protein-damaging stress such as heat shock, because activation of JNK involved inhibition of JNK phosphatase activities. Indeed , expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6. Aggrega-tion of M3/6 by polyglutamine expansion appeared to be indirect, because M3/6 was not recruited into polyglu-tamine inclusions. The heat shock protein HSP70, which is known to inhibit JNK during the heat shock response, suppressed polyglutamine-mediated aggregation of M3/6 and activation of JNK. Interestingly, levels of HSP70 were down-regulated by polyglutamine expansion. We suggest that reduction of HSP70 by expanded polyglutamine is implicated in aggregation and inhibition of M3/6 and in activation of JNK and AP-1.