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dc.contributor.authorLiu, S.
dc.contributor.authorLi, Y.
dc.contributor.authorChoi, H.M.C.
dc.date.accessioned2019-05-21T18:56:24Z
dc.date.available2019-05-21T18:56:24Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85045878870&doi=10.1038%2fs41419-018-0469-1&partnerID=40&md5=6794943b239d54af2f8afa17404e093f
dc.identifier.urihttp://hdl.handle.net/10713/9272
dc.description.abstractNecroptosis, a regulated necrosis pathway mediated by the receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3), is induced following spinal cord injury (SCI) and thought to contribute to neuronal and glial cell death. However, mechanisms leading to activation of necroptosis after SCI remain unclear. We have previously shown that autophagy, a catabolic pathway facilitating degradation of cytoplasmic proteins and organelles in a lysosome-dependent manner, is inhibited following SCI in rats. Our current data confirm that inhibition of autophagy also occurs after thoracic contusive SCI in the mouse model, as indicated by accumulation of both the autophagosome marker, LC3-II and autophagy cargo protein, p62/SQSTM1. This was most pronounced in the ventral horn neurons and was caused by rapid inhibition of lysosomal function after SCI. Interestingly, RIPK1, RIPK3, and the necroptosis effector protein MLKL also rapidly accumulated after SCI and localized to neurons with disrupted autophagy, suggesting that these events may be related. To determine if lysosomal dysfunction could contribute to induction of necroptosis, we treated PC12 cells and primary rat cortical neurons with lysosomal inhibitors. This led to rapid accumulation of RIPK1 and RIPK3, confirming that they are normally degraded by the lysosomal pathway. In PC12 cells lysosomal inhibition also sensitized cells to necroptosis induced by tumor necrosis factor ? (TNF?) and caspase inhibitor. Imaging studies confirmed that RIPK1 partially localized to lysosomes in both untreated and lysosomal inhibitor treated cells. Similarly, we detected presence of RIPK1, RIPK3 and MLKL in both cytosol and at lysosomes after SCI in vivo. Furthermore, stimulation of autophagy and lysosomal function with rapamycin treatment led to decreased accumulation of RIPK1 and attenuated cell death after SCI. These data suggest that lysosomal dysfunction after SCI may contribute to both inhibition of autophagy and sensitize cells to necroptosis by promoting RIPK1 and RIPK3 accumulation. Copyright 2018 The Author(s).en_US
dc.description.sponsorshipThis study was supported by the National Institutes of Health Grants R01 NS094527 to J.W. and M.M.L., R01 NS091218 to M.M.L., and 2R01 NR013601 to J.W.en_US
dc.description.urihttps://dx.doi.org/10.1038/s41419-018-0469-1en_US
dc.language.isoen_USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofCell Death and Disease
dc.subjectnecroptosisen_US
dc.subject.meshSpinal Cord Injuries--physiopathologyen_US
dc.titleLysosomal damage after spinal cord injury causes accumulation of RIPK1 and RIPK3 proteins and potentiation of necroptosisen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41419-018-0469-1


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