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A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.
Ralvenius, William T; Mungenast, Alison E; Woolf, Hannah; Huston, Margaret M; Gillingham, Tyler Z; Godin, Stephen K; Penney, Jay; Cam, Hugh P; Gao, Fan; Fernandez, Celia G; Czako, Barbara; Lightfoot, Yaima; Ray, William J; Beckmann, Adrian; Goate, Alison M; Marcora, Edoardo; Romero-Molina, Carmen; Ayata, Pinar; Schaefer, Anne; Gjoneska, Elizabeta; Tsai, Li-Huei.
Afiliación
  • Ralvenius WT; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Mungenast AE; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Woolf H; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Huston MM; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Gillingham TZ; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Godin SK; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Penney J; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Cam HP; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Gao F; Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Fernandez CG; The Neurodegeneration Consortium, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Czako B; The Neurodegeneration Consortium, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lightfoot Y; The Neurodegeneration Consortium, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ray WJ; The Neurodegeneration Consortium, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Beckmann A; The Neurodegeneration Consortium, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Goate AM; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Marcora E; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai , New York, NY, USA.
  • Romero-Molina C; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Ayata P; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Schaefer A; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai , New York, NY, USA.
  • Gjoneska E; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Tsai LH; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J Exp Med ; 220(11)2023 11 06.
Article en En | MEDLINE | ID: mdl-37642942
Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer's disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Enfermedades Neuroinflamatorias Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Exp Med Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Enfermedades Neuroinflamatorias Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Exp Med Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos