title: TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau.
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.
authors: 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.
authors: Maxime Wc
authors: MW
authors: Rousseaux
authors: 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.
authors: Maria
authors: M
authors: de Haro
authors: 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.
authors: Cristian A
authors: CA
authors: Lasagna-Reeves
authors: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Program in Developmental Biology, Baylor College of Medicine, Houston, Canada.
authors: Antonia
authors: A
authors: De Maio
authors: 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.
authors: Jeehye
authors: J
authors: Park
authors: 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.
authors: Paymaan
authors: P
authors: Jafar-Nejad
authors: 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.
authors: Ismael
authors: I
authors: Al-Ramahi
authors: 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.
authors: Ajay
authors: A
authors: Sharma
authors: 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.
authors: Lauren
authors: L
authors: See
authors: 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.
authors: Nan
authors: N
authors: Lu
authors: 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.
authors: Luis
authors: L
authors: Vilanova-Velez
authors: 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.
authors: Tiemo J
authors: TJ
authors: Klisch
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors: Thomas F
authors: TF
authors: Westbrook
authors: Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States.
authors: Juan C
authors: JC
authors: Troncoso
authors: 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.
authors: Juan
authors: J
authors: Botas
authors: 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.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
authors: Huda Y
authors: 0000-0002-0700-3349
authors: HY
authors: Zoghbi
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D010300:Parkinson Disease / Q000503:physiopathology; D000076183:Tripartite Motif-Containing Protein 28 / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28
keywords: Alzheimer's disease; D. melanogaster; Parkinson's disease; human; mouse; neurodegeneration; neuroscience; synucleinopathies; tauopathies