Pathogenic tau does not drive activation of the unfolded protein response

The unfolded protein response (UPR) is commonly associated with a range of neurodegenerative diseases, and targeting UPR components has been suggested as a therapeutic strategy. The UPR surveys protein folding within the endoplasmic reticulum (ER). However, many of the misfolded proteins that accumulate in neurodegeneration are localized such that they do not directly cause ER triggers that activate this pathway. Here, using a transgenic mouse model and primary cell cultures, along with qPCR, immunoblotting and immunohistochemistry, we tested whether UPR is induced in in vivo andin vitro murine models of tauopathy that are based on expression of mutant tauP301L. We found no evidence for UPR in the rTg4510 mouse model in which mutant tau is transgenically expressed under control oftetracycline-controlled transactivator protein (tTA). This observation was supported by results from acute experiments in which neuronal cultures expressed mutant tau and accumulated misfolded cytoplasmic tau aggregates, but exhibited no UPR activation. These results suggest that the UPR is not induced as a response to tau misfolding and aggregation, despite clear evidence for progressive cellular dysfunction and degeneration. We propose that caution is needed when evaluating the implied significance of the UPR as a critical determinant across major neurodegenerative diseases