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    PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma

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    Author
    Sarkar, C.
    Jones, J.W.
    Hegdekar, N.
    Date
    2019
    Journal
    Autophagy
    Publisher
    Taylor and Francis Inc.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1080/15548627.2019.1628538
    Abstract
    Lysosomal membrane permeabilization (LMP) is observed under many pathological conditions, leading to cellular dysfunction and death. However, the mechanisms by which lysosomal membranes become leaky in vivo are not clear. Our data demonstrate that LMP occurs in neurons following controlled cortical impact induced (CCI) traumatic brain injury (TBI) in mice, leading to impaired macroautophagy (autophagy) and neuronal cell death. Comparison of LC-MS/MS lysosomal membrane lipid profiles from TBI and sham animals suggested a role for PLA2G4A/cPLA2 (phospholipase A2, group IVA [cytosolic, calcium-dependent]) in TBI-induced LMP. Activation of PLA2G4A caused LMP and inhibition of autophagy flux in cell lines and primary neurons. In vivo pharmacological inhibition of PLA2G4A attenuated TBI-induced LMP, as well as subsequent impairment of autophagy and neuronal loss, and was associated with improved neurological outcomes. Inhibition of PLA2G4A in vitro limited amyloid-β-induced LMP and inhibition of autophagy. Together, our data indicate that PLA2G4A -mediated lysosomal membrane damage is involved in neuronal cell death following CCI-induced TBI and potentially in other neurodegenerative disorders. Copyright 2019 The Author(s).
    Keyword
    Amyloid β
    autophagy
    cytosolic phospholipase A2 (cPLA2)
    lysosomal membrane permeabilization (LMP)
    membrane lipidomic analysis
    traumatic brain injury (TBI)
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85068071601&doi=10.1080%2f15548627.2019.1628538&partnerID=40&md5=b5cb9d1c968616eca837823bc99bd637; http://hdl.handle.net/10713/10720
    ae974a485f413a2113503eed53cd6c53
    10.1080/15548627.2019.1628538
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