{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:52:28Z","timestamp":1790805148744,"version":"4.1.0"},"reference-count":60,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. National Institutes of Health","doi-asserted-by":"crossref","award":["R01 NS063967,T32-GM007863,T32-GM007315,T32 NS007222,R01 NS096785"],"award-info":[{"award-number":["R01 NS063967,T32-GM007863,T32-GM007315,T32 NS007222,R01 NS096785"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,15]]},"abstract":"<jats:p>A critical response to lysosomal membrane permeabilization (LMP) is the clearance of damaged lysosomes through a selective form of macroautophagy known as lysophagy. Although regulators of this process are emerging, whether organ- and cell-specific components contribute to the control of lysophagy remains incompletely understood. Here, we examined LMP and lysophagy in Niemann-Pick type C (NPC) disease, an autosomal recessive disorder characterized by the accumulation of unesterified cholesterol within late endosomes and lysosomes, leading to neurodegeneration and early death. We demonstrated that NPC human fibroblasts show enhanced sensitivity to lysosomal damage as a consequence of lipid storage. Moreover, we described a role for the glycan-binding F-box protein 2 (Fbxo2) in CNS lysophagy. Fbxo2 functions as a component of the S phase kinase-associated protein 1\u2013cullin 1\u2013F-box protein (SKP1-CUL1-SCF) ubiquitin ligase complex. Loss of Fbxo2 in mouse primary cortical cultures delayed clearance of damaged lysosomes and decreased viability after lysosomal damage. Moreover, Fbxo2 deficiency in a mouse model of NPC exacerbated deficits in motor function, enhanced neurodegeneration, and reduced survival. Collectively, our data identified a role for Fbxo2 in CNS lysophagy and establish its functional importance in NPC.<\/jats:p>","DOI":"10.1172\/jci.insight.136676","type":"journal-article","created":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T12:00:49Z","timestamp":1600171249000},"source":"Crossref","is-referenced-by-count":49,"title":["Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain"],"prefix":"10.1172","volume":"5","author":[{"given":"Elaine A.","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology,"},{"name":"Cellular and Molecular Biology Graduate Program, and"},{"name":"Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3149-4424","authenticated-orcid":true,"given":"Mark L.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chisaki","family":"Mochida","sequence":"additional","affiliation":[{"name":"Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0510-8996","authenticated-orcid":true,"given":"Chan","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-7535","authenticated-orcid":true,"given":"Henry L.","family":"Paulson","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Lieberman","sequence":"additional","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,10,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3565"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2017.11.012"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12966"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1063871"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2016.08.003"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2009.01415.x"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nature10744"},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms3111","article-title":"Spatiotemporally controlled induction of autophagy-mediated lysosome turnover","volume":"4","author":"Hung","year":"2013","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.10.019"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1702615114"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.23.8247"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0025-4"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq273"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0987-13.2013"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.4"},{"issue":"2","key":"B16","doi-asserted-by":"crossref","DOI":"10.15252\/embj.201899553","article-title":"Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders","volume":"38","author":"Gaband\u00e9-Rodr\u00edguez","year":"2019","journal-title":"EMBO J"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nature08710"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.081096"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw025"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2003.00147.x"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5323.228"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2298"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807328105"},{"key":"B24","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-5-16","article-title":"Niemann-Pick disease type C","volume":"5","author":"Vanier","year":"2010","journal-title":"Orphanet J Rare Dis"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.171"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.1.83"},{"issue":"4","key":"B27","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.bbamcr.2008.08.009","article-title":"Treating lysosomal storage disorders: current practice and future prospects","volume":"1793","author":"Platt","year":"2009","journal-title":"Biochim Biophys Acta"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201695148"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.10.042"},{"issue":"1","key":"B30","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1371\/journal.pgen.0010007","article-title":"Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease","volume":"1","author":"Ko","year":"2005","journal-title":"PLoS Genet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070052"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm100"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds324"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds090"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.03.014"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4173-14.2015"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06115-2"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.25"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011765"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan4183"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708735200"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03316-5"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914309107"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.667469"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nature03029"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3582"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1701734114"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr372"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M709508200"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.52.35222"},{"issue":"36","key":"B51","doi-asserted-by":"crossref","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","article-title":"An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex","volume":"34","author":"Zhang","year":"2014","journal-title":"J Neurosci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602423200"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0206-07.2007"},{"issue":"6384","key":"B54","doi-asserted-by":"crossref","DOI":"10.1126\/science.aar5078","article-title":"Triggered recruitment of ESCRT machinery promotes endolysosomal repair","volume":"360","author":"Skowyra","year":"2018","journal-title":"Science"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006042"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp552"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2010.10.030"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050262"},{"key":"B59","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.mito.2014.06.006","article-title":"Lysosomal membrane permeabilization in cell death: concepts and challenges","volume":"19 Pt A","author":"Repnik","year":"2014","journal-title":"Mitochondrion"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003462"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/136676\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:52:18Z","timestamp":1779151938000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/136676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,15]]},"references-count":60,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10,15]]},"published-print":{"date-parts":[[2020,10,15]]}},"alternative-id":["10.1172\/jci.insight.136676"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.136676","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,15]]},"article-number":"e136676"}}