Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity

Huntington's disease (HD) is an autosomal dominant neurodegenerative disord er caused by polyglutamine expansion in the disease protein, huntingtin, In HD patients and transgenic mice, the affected neurons form characteristic ubiquitin-positive nuclear inclusions (NIs), We have established ecdysone-i nducible stable mouse Neuro2a cell lines that express truncated N-terminal huntingtin (tNhtt) with different polyglutamine lengths which form both cyt oplasmic and nuclear aggregates in a polyglutamine length- and inducer dose -dependent manner, Here we demonstrate that newly synthesized polyglutamine -expanded truncated huntingtin interacts with members of Hsp40 and Hsp70 fa milies of chaperones in a polyglutamine length-dependent manner. Of these i nteracting chaperones, only Hdj-2 and Hsc70 frequently (Hdj-2 > Hsc70) co-l ocalize with both the aggregates in the cellular model and with the NIs in the brains of HD exon 1 transgenic mice, However, Hdj-2 and Hsc70 do not co -localize with cytoplasmic aggregates in the brains of transgenic mice desp ite these chaperones being primarily localized in the cytoplasmic compartme nt, This strongly suggests that the chaperone interaction and their redistr ibution to the aggregates are two completely different phenomena of the cel lular unfolded protein response, This unfolded protein response is also evi dent from the dramatic induction of Hsp70 on expression of polyglutamine-ex panded protein in the cellular model, Transient overexpression of either Hd j-1 or Hsc70 suppresses the aggregate formation; however, suppression effic iency is much higher in Hdj-1 compared with Hsc70, Overexpression of Hdj-1 and Hsc70 is also able to protect cell death caused by polyglutamine-expand ed tNhtt and their combination proved to be most effective.