Hsp40 molecular chaperones are potent regulators of tau seeding and accumulation

Abstract

AbstractBackgroundThe misfolding of the microtubule associated protein tau is associated with Alzheimer’s disease and other tauopathies. In tauopathies, aberrant tau spreads through synaptically connected regions of the brain by templating the misfold of endogenous tau. Work from our group and others has identified molecular chaperones as regulators of tau accumulation and toxicity, but many tau regulators have yet to be identified.MethodWe performed a screen of members from seven major chaperone families using Tau RD P301S FRET Biosensor cells. Hits were assessed by secondary knockdown studies in cultured cells and validated in tau expressing primary neurons. Additional in vitro experiments to dissect the mechanism of activity are ongoing, which will be followed by in vivo studies.ResultOur data support the use of Tau RD P301S FRET Biosensor cells as a robust screening tool to identify known and novel tau regulators. The Hsp40 family is enriched with tau regulators, including some not previously known to affect tau. Studies are ongoing to determine how these proteins alter tau levels.ConclusionMultiple members of the Hsp40 family regulate tau accumulation.