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    cPLA2 activation contributes to lysosomal defects leading to impairment of autophagy after spinal cord injury

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    Author
    Li, Y.
    Jones, J.W.
    M., C., Choi, H.
    Date
    2019
    Journal
    Cell Death and Disease
    Publisher
    Nature Publishing Group
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1038/s41419-019-1764-1
    Abstract
    The autophagy-lysosomal pathway plays an essential role in cellular homeostasis as well as a protective function against a variety of diseases including neurodegeneration. Conversely, inhibition of autophagy, for example due to lysosomal dysfunction, can lead to pathological accumulation of dysfunctional autophagosomes and consequent neuronal cell death. We previously reported that autophagy is inhibited and contributes to neuronal cell death following spinal cord injury (SCI). In this study, we examined lysosomal function and explored the mechanism of lysosomal defects following SCI. Our data demonstrated that expression levels and processing of the lysosomal enzyme cathepsin D (CTSD) are decreased by 2 h after SCI. Enzymatic activity levels of CTSD and another lysosomal enzyme, N-acetyl-alpha-glucosaminidase, are both decreased 24 h post injury, indicating general lysosomal dysfunction. Subcellular fractionation and immunohistochemistry analysis demonstrated that this dysfunction is due to lysosomal membrane permeabilization and leakage of lysosomal contents into the cytosol. To directly assess extent and mechanisms of damage to lysosomal membranes, we performed mass spectrometry-based lipidomic analysis of lysosomes purified from SCI and control spinal cord. At 2 h post injury our data demonstrated increase in several classes of lysosophospholipids, the products of phospholipases (PLAs), as well as accumulation of PLA activators, ceramides. Phospholipase cPLA2, the main PLA species expressed in the CNS, has been previously implicated in mediation of secondary injury after SCI, but the mechanisms of its involvement remain unclear. Our data demonstrate that cPLA2 is activated within 2 h after SCI preferentially in the lysosomal fraction, where it colocalizes with lysosomal-associated membrane protein 2 in neurons. Inhibition of cPLA2 in vivo decreased lysosomal damage, restored autophagy flux, and reduced neuronal cell damage. Taken together our data implicate lysosomal defects in pathophysiology of SCI and for the first time indicate that cPLA2 activation leads to lysosomal damage causing neuronal autophagosome accumulation associated with neuronal cell death. Copyright 2019, The Author(s).
    Sponsors
    This study was supported by the National Institutes of Health Grants R01 NS094527, 2R01 NR013601, R01 NS110635, and R01 NS110567 to J.W., R01 NS091218 to M.M.L.
    Keyword
    SCI
    lysosomal dysfunction
    lysosomal enzyme
    Cathespin D
    CTSD
    phospholipase cPLA2
    Spinal Injuries
    Autophagy
    Phospholipases A2, Cytosolic
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85068817870&doi=10.1038%2fs41419-019-1764-1&partnerID=40&md5=9bed1b226aac89bde00c28b1527f5dd0; http://hdl.handle.net/10713/10592
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41419-019-1764-1
    Scopus Count
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    UMB Open Access Articles 2019

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