Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY/ABSTRACT Tauopathies are a growing group of neurodegenerative disorders, including Alzheimer’s disease and mul- tiple related dementias, and are characterized by intracellular deposition of tau aggregates. Absence of tau mutations in the vast majority of tauopathy patients, and all of Alzheimer’s disease cases, highlights a critical need to understand why the tau protein fails to retain its native conformation, and forms pathogenic aggre- gates. The objective of the proposed research is to identify a common molecular mechanism underlying tau proteostasis, and to determine in vivo how this mechanism modifies tau aggregation and neurodegeneration: Chaperones are key mediators of proteostasis, and the chaperone protein Hsc70 is known to bind tau directly. However, the fate of Hsc70-bound clients is determined by co-chaperones, assembled into chaperone com- plexes. We have identified two chaperone-complexes that affect tau in diametrically opposite directions: CSPα/Hsc70/SGT/Hsp90 containing “foldase” complex and Hsj1/Hsc70/CHIP containing “degradase” complex. This study will test the hypothesis that tau protein levels, aggregation and neurodegeneration are regulated by these two chaperone machines/complexes: the foldase complex stabilizes tau and the degradase complex tar- gets tau for degradation, and tau pathology can be manipulated by these activities. We will test this hypothesis in vitro, in primary neurons, and in mouse models of tauopathies in vivo. Completion of these studies is ex- pected to identify two new molecular processes which affect tau aggregation, as well as to reveal how these proteostatic activities affect tau pathology in vivo. The proposed study is innovative, because two new func- tions of the foldase and degradase chaperone complexes on their new client tau are proposed, and because of the use of a comprehensive experimental approach, including: a) a new primary neuron tau aggregation model, b) viral approaches for CRISPR/Cas9-knockout of co-chaperones in primary neurons, c) stereotactic injections to virally regulate the co-chaperone levels in vivo, d) using patient brain samples to establish rele- vance of our findings to tauopathy in Alzheimer’s disease. The proposed study is significant because a) the concept of multifaceted proteostasis, where tau aggregation is affected by the equilibrium between “degradase” and “foldase” mechanisms, can be readily translated to other proteins related to Alzheimer’s dis- ease and related dementias (e.g. TDP43 or α-synuclein), b) understanding how neurons prevent tau from ag- gregating will establish novel targets for treating tauopathies, and c) understanding cellular proteostasis mech- anisms of misfolding-prone proteins may reveal clues common to the sporadic versions of tauopathies, includ- ing Alzheimer’s disease, for which tau mutations are not the most robust or common risk factor. This grant thus addresses the Notice of Special Interest NOT-AG-21-037: Common Mechanisms and Interactions in Neuro- degenerative Diseases.
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