TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau
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
Affiliations
Maxime WC Rousseaux
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
Maria de Haro
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
Cristian A Lasagna-Reeves
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
Antonia De Maio
Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States; Program in Developmental Biology, Baylor College of Medicine, Houston, Canada
Jeehye Park
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
Paymaan Jafar-Nejad
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
Ismael Al-Ramahi
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
Ajay Sharma
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
Lauren See
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
Nan Lu
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
Luis Vilanova-Velez
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
Tiemo J Klisch
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
Thomas F Westbrook
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
Juan C Troncoso
Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States
Juan Botas
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
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
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.
