TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau.

ABSTRACT: Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (?-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that ?-Syn and tau overlap pathologically. The connections between ?-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of ?-Syn and tau. We found that TRIM28 regulates ?-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and ?-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points.

SUBMITTER: Rousseaux MW 

PROVIDER: S-EPMC5104516 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature