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dc.contributor.authorLi, Y.
dc.contributor.authorJones, J.W.
dc.contributor.authorM., C., Choi, H.
dc.date.accessioned2019-09-13T14:49:31Z
dc.date.available2019-09-13T14:49:31Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85068817870&doi=10.1038%2fs41419-019-1764-1&partnerID=40&md5=9bed1b226aac89bde00c28b1527f5dd0
dc.identifier.urihttp://hdl.handle.net/10713/10592
dc.description.abstractThe 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).en_US
dc.description.sponsorshipThis 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.en_US
dc.description.urihttps://doi.org/10.1038/s41419-019-1764-1en_US
dc.language.isoen-USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofCell Death and Disease
dc.subjectSCIen_US
dc.subjectlysosomal dysfunctionen_US
dc.subjectlysosomal enzymeen_US
dc.subjectCathespin Den_US
dc.subjectCTSDen_US
dc.subjectphospholipase cPLA2en_US
dc.subject.meshSpinal Injuriesen_US
dc.subject.meshAutophagyen_US
dc.subject.meshPhospholipases A2, Cytosolicen_US
dc.titlecPLA2 activation contributes to lysosomal defects leading to impairment of autophagy after spinal cord injuryen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41419-019-1764-1


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