Hsp70/DnaJ interface as a drug target for Alzheimer's disease and TBI

James A. Haley Va Medical Center, Tampa FL

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Abstract

DESCRIPTION (provided by applicant): Accumulation of the microtubule associated protein tau is associated with neuronal death in Alzheimer's disease (AD), Parkinson's disease and traumatic brain injury (TBI). Therefore tau is a tractable therapeutic target for each of these diseases. The chaperone family of proteins, and in particular the heat shock protein 70 family, is critical for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is strongly associated with granulovacuolar degenerating bodies (GVDs), which are major tau-associated pathological entities in AD neurons that are linked to autophagic clearance mechanisms. Co-localization studies have also shown that Hsp73 associates with accumulated tau in the brain. However, the actual mechanisms involving the Hsp70 family with tau biology have been challenging to define. Hsp70 proteins can either promote tau clearance or functionally preserve it. Recently, we have begun to elucidate the reason for this dichotomy. We have found that Hsp70 proteins act to seek out, identify and hold onto tau, but other chaperones termed DnaJ proteins by manipulating substrate selection and Hsp70 ATPase activity dictate whether this Hsp70-bound tau should be preserved, sequestered or destroyed. Therefore, we will test the hypothesis that regulation of tau triage by Hsp70 proteins is mediated through the Hsp70/DnaJ interface by: 1) determining whether chemical modulation of the DnaJ- binding domain on Hsp70 proteins regulates tau stability in vivo; 2) determining whether genetic modulation of the DnaJ-binding domain on Hsp73 regulates tau stability in vivo; and 3) determining whether modulating discreet DnaJ proteins directly can regulate tau processing in vivo. Successful completion of these studies will prove the relevance of the DnaJ/Hsp70 interface as a possible treatment for AD, PD, TBI and more than 15 other neurodegenerative diseases termed tauopathies.