The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP–protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.
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We thank J. Lewis and K. Ashe for providing rTg4510 and JNPL3 mice and P. Davies for the generous gift of tau antibodies. We thank L. Liu for assisting with mice perfusion. This work was supported by grants from the US National Institute of Neurological Disorders and Stroke NS074593 (K.E.D.), CurePSP Foundation (N.M.), the US National Institute of General Medical Sciences GM051923 (to A.L.G.), the Fidelity Biosciences Research Initiative (A.L.G.) and the Multiple Myeloma Research Foundation (N.V.K.).
The authors declare no competing financial interests.
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Myeku, N., Clelland, C., Emrani, S. et al. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med 22, 46–53 (2016). https://doi.org/10.1038/nm.4011
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