TRIM28 Regulates the Nuclear Accumulation and Toxicity of Both Alpha-Synuclein and Tau

Elife. 2016 Oct 25;5:e19809. doi: 10.7554/eLife.19809.

Abstract

Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-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 α-Syn and tau overlap pathologically. The connections between α-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 α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-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.

Keywords: Alzheimer's disease; D. melanogaster; Parkinson's disease; human; mouse; neurodegeneration; neuroscience; synucleinopathies; tauopathies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / physiopathology
  • Animals
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Mice
  • Parkinson Disease / physiopathology
  • Tripartite Motif-Containing Protein 28 / metabolism*
  • alpha-Synuclein / metabolism*
  • tau Proteins / metabolism*

Substances

  • MAPT protein, human
  • alpha-Synuclein
  • tau Proteins
  • TRIM28 protein, human
  • Tripartite Motif-Containing Protein 28