We studied the ability of heat shock, DnaJ-like-1 (HSJ1)
proteins (which contain DnaJ and
ubiquitin-interacting motifs) to reduce
polyglutamine-mediated inclusion formation. The experiments demonstrated that expression of
heat shock protein 70 (hsp70), hsp40, HSJ1a, and HSJ1b significantly reduced
protein inclusion formation in a model of
spinal and bulbar muscular atrophy (SBMA). HSJ1a also mediated a significant decrease in the number of inclusions formed in a primary neuronal model of
protein aggregation. Studies to elucidate the mechanisms underlying these reductions showed that hsp70 and hsp40 increased chaperone-mediated refolding. In contrast, expression of HSJ1
proteins did not promote chaperone activity but caused an increase in ubiquitylation. Furthermore, HSJ1a was associated with a ubiquitylated
luciferase complex, and in the presence of HSJ1a but not an HSJ1a UIM mutant (HSJ1a-ΔUIM) there was a reduction in
luciferase protein levels. Together these results show that HSJ1
proteins mediated an increase in target protein degradation via the
ubiquitin-
proteasome system (UPS). We also found that the expression of HSJ1a significantly decreased the number of neurons containing inclusions in an in vivo model of
polyglutamine disease. These findings indicate that targeted modification of the UPS to facilitate degradation of misfolded
proteins may represent a highly effective therapeutic avenue for the treatment of
polyglutamine disease.