Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia
Funes, Salome ; Jung, Jonathan ; Gadd, Del Hayden ; Mosqueda, Michelle ; Zhong, Jianjun ; Shankaracharya ; Unger, Matthew ; Stallworth, Karly ; Cameron, Debra ; Rotunno, Melissa S ... show 10 more
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Authors
Jung, Jonathan
Gadd, Del Hayden
Mosqueda, Michelle
Zhong, Jianjun
Shankaracharya
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
Student Authors
Michelle Mosqueda
Jonathan Jung
Matthew Unger
Faculty Advisor
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UMass Chan Affiliations
Brudnick Neuropsychiatric Research Institute
Genomics and Computational Biology
Horae Gene Therapy Center
Microbiology and Physiological Systems
Molecular, Cell and Cancer Biology
Morningside Graduate School of Biomedical Sciences
Neurobiology
Neurology
Pediatrics
Schafer Lab
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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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Funes S, Jung J, Gadd DH, Mosqueda M, Zhong J, Shankaracharya, Unger M, Stallworth K, Cameron D, Rotunno MS, Dawes P, Fowler-Magaw M, Keagle PJ, McDonough JA, Boopathy S, Sena-Esteves M, Nickerson JA, Lutz C, Skarnes WC, Lim ET, Schafer DP, Massi F, Landers JE, Bosco DA. Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia. Nat Commun. 2024 Mar 20;15(1):2497. doi: 10.1038/s41467-024-46695-w. PMID: 38509062; PMCID: PMC10954694.
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This article is based on a previously available preprint in bioRxiv, https://doi.org/10.1101/2023.06.01.541136