TSC1loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

Abstract

Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), are collectively known as tauopathies. The vast majority of human tauopathies accumulate non-mutant tau rather than mutant forms of the protein, yet cell and animal models for non-mutant tauopathies are lacking. We previously linked a monoallelic mutation in the TSC1 gene to tau accumulation and FTLD. Now, we have identified new variants in TSC1 that predisposed to other tauopathies such as AD and PSP. These new TSC1 risk variants significantly decreased the half-life of TSC1/hamartin in vitro. Cellular and murine models of TSC1 haploinsufficiency (TSC1+/-) accumulated tau protein that exhibited aberrant acetylation on six lysine residues. Tau acetylation hindered its lysosomal degradation via chaperone-mediated autophagy leading to neuronal tau accumulation. Enhanced tau acetylation in TSC1+/- models was achieved through both an increase in p300 acetyltransferase activity and a decrease in SIRT1 deacetylase levels. Pharmacological modulation of either enzyme restored tau levels. Together, these studies substantiate TSC1 as a novel tauopathy risk gene and advance TSC1 haploinsufficiency as a new genetic model for tauopathy. In addition, these results promote acetylated tau as a rational target for diagnostic and therapeutic modalities in multiple tauopathies.

Altered Cerebrospinal Fluid Exosomal microRNA Levels in Young-Onset Alzheimer’s Disease and Frontotemporal Dementia

“…Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) functions as a translation repressor protein, and phosphorylated EIF4EBP1 levels have been reported to be significantly increased in AD brains compared to controls [35], while increased levels have been found in the CSF and plasma of AD patients [36]. Interestingly, tuberous sclerosis protein 1 (TSC1) has been genetically linked with AD, while loss of TSC1 is associated with tauopathy in in vitro and in vivo studies [37,38]. Protein Phosphatase 2 Regulatory Subunit B'Delta (PPP2R5D) has also been associated with tau hyperphosphorylation [39,40] and studies have reported decreased PPP2R5D expression and activity in the AD hippocampus [41,42].…”