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    Investigating Cell-Autonomous Mechanisms of Microglia Dysfunction in PFN1-ALS

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    Name:
    Thesis Salome Funes uploaded ...
    Embargo:
    2024-10-21
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    Authors
    Funes, Salome cc
    Faculty Advisor
    Daryl Bosco
    Academic Program
    Translational Science
    UMass Chan Affiliations
    Neurology
    Document Type
    Doctoral Dissertation
    Publication Date
    2022-10-19
    Keywords
    ALS
    Microglia
    iPSC
    phagocytosis
    
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    Abstract
    Amyotrophic 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.
    DOI
    10.13028/r1n4-d529
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51202
    Rights
    Copyright © 2022 Funes.
    Distribution License
    All Rights Reserved
    ae974a485f413a2113503eed53cd6c53
    10.13028/r1n4-d529
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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