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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.

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


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.


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

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