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Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.
Funes, Salome; Jung, Jonathan; Gadd, Del Hayden; Mosqueda, Michelle; Zhong, Jianjun; Unger, Matthew; Stallworth, Karly; Cameron, Debra; Rotunno, Melissa S; Dawes, Pepper; Fowler-Magaw, Megan; Keagle, Pamela J; McDonough, Justin A; Boopathy, Sivakumar; Sena-Esteves, Miguel; Nickerson, Jeffrey A; Lutz, Cathleen; Skarnes, William C; Lim, Elaine T; Schafer, Dorothy P; Massi, Francesca; Landers, John E; Bosco, Daryl A.
Afiliação
  • Funes S; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Jung J; Translational Science Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Gadd DH; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Mosqueda M; Neuroscience Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Zhong J; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Shankaracharya; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Unger M; Biochemistry and Molecular Biotechnology Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Stallworth K; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Cameron D; Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • Rotunno MS; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Dawes P; Biochemistry and Molecular Biotechnology Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Fowler-Magaw M; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Keagle PJ; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • McDonough JA; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Boopathy S; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Sena-Esteves M; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Nickerson JA; Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Lutz C; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Skarnes WC; Neuroscience Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Lim ET; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Schafer DP; The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
  • Massi F; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Landers JE; Biochemistry and Molecular Biotechnology Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Bosco DA; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Nat Commun ; 15(1): 2497, 2024 Mar 20.
Article em En | MEDLINE | ID: mdl-38509062
ABSTRACT
Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Neurodegenerativas / Células-Tronco Pluripotentes Induzidas / Esclerose Lateral Amiotrófica Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Neurodegenerativas / Células-Tronco Pluripotentes Induzidas / Esclerose Lateral Amiotrófica Limite: Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos