Polyglutamine diseases, including Huntington's disease, designate a group of 
nine neurodegenerative disorders characterized by the presence of a toxic 
polyglutamine expansion in specific target proteins. Using cell and mouse 
models, we have shown that expanded polyglutamine 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. Aggregation of M3/6 by polyglutamine expansion appeared to be indirect, 
because M3/6 was not recruited into polyglutamine 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.