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

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
2
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
3
Program in Developmental Biology, Baylor College of Medicine, Houston, Canada.
4
The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
5
Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States.
6
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.

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

PMID:
27779468
PMCID:
PMC5104516
DOI:
10.7554/eLife.19809
[Indexed for MEDLINE]
Free PMC Article

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