Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects.

ABSTRACT: Tau pathology is associated with cognitive decline in Alzheimer's disease, and missense tau mutations cause frontotemporal dementia. Hyperphosphorylation and misfolding of tau are considered critical steps leading to tauopathies. Here, we determine how motifs controlling conformational changes in the microtubule-binding domain determine tau pathology in vivo. Human tau was overexpressed in the adult mouse forebrain to compare variants carrying residues that modulate tau propensity to acquire a β-sheet conformation. The P301S mutation linked to frontotemporal dementia causes tau aggregation and rapidly progressing motor deficits. By comparison, wild-type tau becomes heavily hyperphosphorylated, and induces behavioral impairments that do not progress over time. However, the behavioral defect

SUBMITTER: Lathuiliere A 

PROVIDER: S-EPMC5648870 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature