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dc.contributor.advisorDaryl Boscoen_US
dc.contributor.authorFunes, Salome
dc.date.accessioned2022-10-25T16:51:18Z
dc.date.available2022-10-25T16:51:18Z
dc.date.issued2022-10-19
dc.identifier.doi10.13028/r1n4-d529en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51202
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons. Cumulative evidence shows that microglia contribute to disease progression, but the underlying mechanisms are unclear. Several ALS-related genes are highly expressed in microglia compared to neurons, including profilin-1 (PFN1). This raises the possibility that ALS-linked PFN1 mutations could induce microglia cell-autonomous dysfunction. Here, I sought to interrogate this possibility by differentiating human pluripotent stem cells (iPSCs) into microglia-like cells (iMGs). My work uncovered that ALS-PFN1 iMGs accumulate undegraded phagocytosed cargo in endo-lysosomal compartments which is recapitulated in vivo. ALS-PFN1 iMGs also exhibit dysregulation in the expression and cellular localization of crucial components of the endo-lysosomal pathway, impairments in the autophagy flux, and accumulation of lipid droplets. Intriguingly, rapamycin treatment ameliorates the accumulation of phagocytosed material in ALS-PFN1 iMGs and rescues the defects in the autophagy pathway, suggesting that an impaired autophagy flux contributes to ALS-PFN1-linked defects in microglial phagocytosis. In vitro experimentation uncovered that PFN1 interacts with phosphatidylinositol-3phosphate, a signaling molecule essential for autophagy and phagocytosis, and that this interaction is altered when PFN1 is mutated in ALS. Collectively, these findings implicate that ALS-PFN1 causes microglia dysfunction by hindering the autophagy flux, perturbing the endo-lysosomal pathway, and, in turn, causing delays in the degradation process during phagocytosis and inducing lipid dysmetabolism. These alterations may be partially driven by ALS-PFN1 distorted interactions with phosphoinositides. My work provides insight into PFN1 biology and opens new perspectives regarding microglia cell-autonomous defects in ALS that may contribute to neurodegeneration.en_US
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2022 Funes.en_US
dc.rights.uriAll Rights Reserveden_US
dc.subjectALSen_US
dc.subjectMicrogliaen_US
dc.subjectiPSCen_US
dc.subjectphagocytosisen_US
dc.titleInvestigating Cell-Autonomous Mechanisms of Microglia Dysfunction in PFN1-ALSen_US
dc.typeDoctoral Dissertationen_US
atmire.contributor.authoremailsalome.funes@umassmed.eduen_US
dc.contributor.departmentNeurologyen_US
dc.description.thesisprogramTranslational Scienceen_US
dc.identifier.orcid0000-0001-6531-4279en_US


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