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    Studies on Matrix-Metalloproteinase 13 as a Novel Microglial Inflammatory Agent in Familial Synucleinopathy

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    View/Open: Sanchez_georgetown_0076D_14760.pdf (5.8MB)

    Creator
    Sanchez, Kathryn E.
    Advisor
    Maguire-Zeiss, Kathleen A.
    Abstract
    α-Synuclein is a 140-amino acid protein highly expressed in presynaptic terminals and is also associated with Lewy body pathology found in Lewy Body Dementia (LBD) and Parkinson’s disease (PD) patients. We and others have shown that α-synuclein is a damage associated molecular pattern (DAMP) that directly elicits a proinflammatory response in microglia (i.e., upregulation of tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL1β), MMP9). α-Synuclein also increases microglial expression of MMP13, an endopeptidase that remodels the extracellular matrix. To better understand the role of MMP13 in synucleinopathies and which cell type is impacted, we used primary mouse cultures. Here we show that cMMP13 did not directly affect hippocampal neuron structure or cytoskeletal proteins. However, exposure of microglia to cMMP13 did lead to morphological changes as well as the release of proinflammatory molecules such as TNFα and MMP-9. Notably, IL1β was not released indicating that the pathway involved in MMP13 activation may be inflammasome independent. Future work will focus on measures of microglial function such as phagocytosis and process motility to better investigate the impact of this MMP on microglia.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1060737
    Date Published
    2020
    Subject
    A53T; Microglia; MMP13; MMP9; TLRs; α-synuclein; Neurobiology; Neurobiology;
    Type
    thesis
    Embargo Lift Date
    2023-01-29
    Publisher
    Georgetown University
    Extent
    200 leaves
    Collections
    • Graduate Theses and Dissertations - Biology
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility