Rousseaux, M.W., de Haro, M., Lasagna-Reeves, C.A., De Maio, A., Park, J., Jafar-Nejad, P., Al-Ramahi, I., Sharma, A., See, L., Lu, N., Vilanova-Velez, L., Klisch, T.J., Westbrook, T.F., Troncoso, J.C., Botas, J., Zoghbi, H.Y. (2016). TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau.  eLife 5(): e19809.

FBrf0239617

Research paper

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.

PMC5104516 (PMC) (EuropePMC)