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dc.contributor.authorFunes, Salome
dc.contributor.authorGadd, Del Hayden
dc.contributor.authorMosqueda, Michelle
dc.contributor.authorZhong, Jianjun
dc.contributor.authorJung, Jonathan
dc.contributor.authorShankaracharya
dc.contributor.authorUnger, Matthew
dc.contributor.authorCameron, Debra
dc.contributor.authorDawes, Pepper
dc.contributor.authorKeagle, Pamela J
dc.contributor.authorMcDonough, Justin A
dc.contributor.authorBoopathy, Sivakumar
dc.contributor.authorSena-Esteves, Miguel
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.accessioned2023-08-15T15:14:45Z
dc.date.available2023-08-15T15:14:45Z
dc.date.issued2023-06-01
dc.identifier.citationFunes S, Gadd DH, Mosqueda M, Zhong J, Jung J, Shankaracharya, Unger M, Cameron D, Dawes P, Keagle PJ, McDonough JA, Boopathy S, Sena-Esteves M, 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. bioRxiv [Preprint]. 2023 Jun 1:2023.06.01.541136. doi: 10.1101/2023.06.01.541136. PMID: 37398081; PMCID: PMC10312575.en_US
dc.identifier.doi10.1101/2023.06.01.541136en_US
dc.identifier.pmid37398081
dc.identifier.urihttp://hdl.handle.net/20.500.14038/52415
dc.descriptionThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.en_US
dc.description.abstractMicroglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be fully 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 lipid dysmetabolism and deficits in phagocytosis, a critical microglia function. Our cumulative data implicate an effect of ALS-linked PFN1 on the autophagy pathway, including enhanced binding of mutant PFN1 to the autophagy signaling molecule PI3P, as an underlying cause of defective phagocytosis in ALS-PFN1 iMGs. Indeed, phagocytic processing was restored in ALS-PFN1 iMGs with Rapamycin, an inducer of autophagic flux. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and highlight microglia vesicular degradation pathways as potential therapeutic targets for these disorders.en_US
dc.language.isoenen_US
dc.relationNow published in Nature Communications doi: 10.1038/s41467-024-46695-w
dc.relation.ispartofbioRxiven_US
dc.relation.urlhttps://doi.org/10.1101/2023.06.01.541136en_US
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.en_US
dc.subjectNeuroscienceen_US
dc.subjectamyotrophic lateral sclerosis (ALS)en_US
dc.subjectmicrogliaen_US
dc.subjectpathogenesisen_US
dc.subjectmutationsen_US
dc.titleExpression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia [preprint]en_US
dc.typePreprinten_US
dc.source.journaltitlebioRxiv : the preprint server for biology
dc.source.countryUnited States
dc.identifier.journalbioRxiv : the preprint server for biology
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.contributor.departmentBrudnick Neuropsychiatric Research Instituteen_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.departmentProgram in Bioinformatics and Integrative Biologyen_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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