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.
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Authors | Maxime Wc Rousseaux, Maria de Haro, Cristian A Lasagna-Reeves, Antonia De Maio, Jeehye Park, Paymaan Jafar-Nejad, Ismael Al-Ramahi, Ajay Sharma, Lauren See, Nan Lu, Luis Vilanova-Velez, Tiemo J Klisch, Thomas F Westbrook, Juan C Troncoso, Juan Botas, Huda Y Zoghbi |
Journal | eLife
(Elife)
Vol. 5
(10 25 2016)
ISSN: 2050-084X [Electronic] England |
PMID | 27779468
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
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Chemical References |
- MAPT protein, human
- alpha-Synuclein
- tau Proteins
- TRIM28 protein, human
- Tripartite Motif-Containing Protein 28
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Topics |
- 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)
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