TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy.

ABSTRACT: Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions are known as tauopathies. We previously linked a loss-of-function mutation in the TSC1 gene to tau accumulation and frontotemporal lobar degeneration. Now, we have identified genetic variants in TSC1 that decrease TSC1/hamartin levels and predispose to tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Cellular and murine models of TSC1 haploinsufficiency, as well as human brains carrying a TSC1 risk variant, accumulated tau protein that exhibited aberrant acetylation. This acetylation hindered tau degradation via chaperone-mediated autophagy, thereby leading to its accumulation. Aberrant tau acetylation in TSC1 haploinsufficiency resulted

SUBMITTER: Alquezar C 

PROVIDER: S-EPMC8570595 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature