TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau
- Baylor College of Medicine, United States
- Texas Children's Hospital, United States
- The University of Toronto, Canada
- Ionis Pharmaceuticals, United States
- Johns Hopkins University School of Medicine, 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.
Article and author information
Author details
Funding
Howard Hughes Medical Institute
- Huda Y Zoghbi
Michael J. Fox Foundation for Parkinson's Research (Target Validation Program 2014)
- Huda Y Zoghbi
Canadian Institutes of Health Research (201210MFE-290072-173743)
- Maxime WC Rousseaux
National Institutes of Health (1K22NS092688-01)
- Cristian A Lasagna-Reeves
National Institutes of Health (U54 HD083092)
- Huda Y Zoghbi
National Institutes of Health (P50 NS38377)
- Juan C Troncoso
National Institutes of Health (P50 AG05146)
- Juan C Troncoso
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Up to five mice were housed per cage and kept on a 12 h light; 12 h dark cycle and were given water and standard rodent chow ad libitum. All procedures carried out in mice were approved by the Institutional Animal Care and Use Committee for Baylor College of Medicine and Affiliates.
Human subjects: Tissue from patients with PD, AD, PSP and control subjects were obtained from the Neuropathology Core at the Johns Hopkins Udall Centre. Tissue was obtained from consenting donors and use conformed to JHMI Institutional Review Board approved protocols.
Copyright
© 2016, Rousseaux et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau
eLife 5:e19809.
https://doi.org/10.7554/eLife.19809
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