Contact Us

What is JoVE Visualize?

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Affiliations
  • 1Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7Department of Genetics & Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • 9Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 10Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 11Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
  • 13Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 14Department of Neurology, Ludwig-Maximilians-Universität Hospital, Munich, Germany.
  • 15Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 16German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 17Institute of Human Genetics, Justus-Liebig University Giessen, 35392, Giessen, Germany.
  • 18Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
  • 19CurePSP, Inc., New York, NY, USA.
  • 20Department of Clinical and Movement Neurosciences, University College London, London, UK.
  • 21Queen Square Institute of Neurology, University College London, London, UK.
  • 22Dementia Research Institute, University College London, London, UK.
  • 23Queen Square Brain Bank for Neurological Disorders, University College London, London, UK.
  • 24VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
  • 25Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • 26Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • 27Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 28Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • 29Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • 30Center for Autism Research and Treatment Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
  • 31Institute for Precision Health, University of California, Los Angeles, CA, USA.
  • 32Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. John.crary@mountsinai.org.
  • 33Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. John.crary@mountsinai.org.
  • 34Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. John.crary@mountsinai.org.
  • 35Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. John.crary@mountsinai.org.
  • 36Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. John.crary@mountsinai.org.
  • 37Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA. John.crary@mountsinai.org.
  • 38Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Adamnaj@pennmedicine.upenn.edu.
  • 39Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Adamnaj@pennmedicine.upenn.edu.
  • 40Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Adamnaj@pennmedicine.upenn.edu.

|

September 9, 2024

Abstract

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.