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dc.contributor.authorFunes, Salome
dc.contributor.authorJung, Jonathan
dc.contributor.authorGadd, Del Hayden
dc.contributor.authorMosqueda, Michelle
dc.contributor.authorZhong, Jianjun
dc.contributor.authorShankaracharya
dc.contributor.authorUnger, Matthew
dc.contributor.authorStallworth, Karly
dc.contributor.authorCameron, Debra
dc.contributor.authorRotunno, Melissa S
dc.contributor.authorDawes, Pepper
dc.contributor.authorFowler-Magaw, Megan
dc.contributor.authorKeagle, Pamela J
dc.contributor.authorMcDonough, Justin A
dc.contributor.authorBoopathy, Sivakumar
dc.contributor.authorSena-Esteves, Miguel
dc.contributor.authorNickerson, Jeffrey A
dc.contributor.authorLutz, Cathleen
dc.contributor.authorSkarnes, William C
dc.contributor.authorLim, Elaine T
dc.contributor.authorSchafer, Dorothy P
dc.contributor.authorMassi, Francesca
dc.contributor.authorLanders, John E
dc.contributor.authorBosco, Daryl A
dc.date.accessioned2024-05-20T19:18:43Z
dc.date.available2024-05-20T19:18:43Z
dc.date.issued2024-03-20
dc.identifier.citationFunes 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.en_US
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-024-46695-wen_US
dc.identifier.pmid38509062
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53350
dc.description.abstractMicroglia 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.en_US
dc.language.isoenen_US
dc.relationThis article is based on a previously available preprint in bioRxiv, https://doi.org/10.1101/2023.06.01.541136en_US
dc.relation.ispartofNature Communicationsen_US
dc.relation.urlhttps://doi.org/10.1038/s41467-024-46695-wen_US
dc.rightsOpen Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2024; Attribution 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAmyotrophic lateral sclerosisen_US
dc.subjectMicrogliaen_US
dc.titleExpression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microgliaen_US
dc.typeJournal Articleen_US
dc.source.journaltitleNature communications
dc.source.volume15
dc.source.issue1
dc.source.beginpage2497
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.identifier.journalNature communications
refterms.dateFOA2024-05-20T19:18:45Z
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.contributor.departmentBrudnick Neuropsychiatric Research Instituteen_US
dc.contributor.departmentGenomics and Computational Biologyen_US
dc.contributor.departmentHorae Gene Therapy Centeren_US
dc.contributor.departmentMicrobiology and Physiological Systemsen_US
dc.contributor.departmentMolecular, Cell and Cancer Biologyen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeurobiologyen_US
dc.contributor.departmentNeurologyen_US
dc.contributor.departmentPediatricsen_US
dc.contributor.departmentSchafer Lab
dc.contributor.studentSalome Funes
dc.contributor.studentMichelle Mosqueda
dc.contributor.studentJonathan Jung
dc.contributor.studentMatthew Unger
dc.description.thesisprogramTranslational Science
dc.description.thesisprogramBiochemistry and Molecular Biotechnology
dc.description.thesisprogramNeuroscience


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Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2024; Attribution 4.0 International
Except where otherwise noted, this item's license is described as Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2024; Attribution 4.0 International