{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:44:35Z","timestamp":1790351075530,"version":"4.1.0"},"reference-count":75,"publisher":"National Academy of Sciences","issue":"44","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R00 NS109252"],"award-info":[{"award-number":["R00 NS109252"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["3R00 NS109252-04S2"],"award-info":[{"award-number":["3R00 NS109252-04S2"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R24 NS098523"],"award-info":[{"award-number":["R24 NS098523"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R37 NS054154"],"award-info":[{"award-number":["R37 NS054154"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS104295"],"award-info":[{"award-number":["R01 NS104295"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NIH HEAL initiative supplement R01 NS104295-01"],"award-info":[{"award-number":["NIH HEAL initiative supplement R01 NS104295-01"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 AR077691"],"award-info":[{"award-number":["R01 AR077691"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,10,31]]},"abstract":"<jats:p>Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria\u2013lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot\u2013Marie\u2013Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria\u2013lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot\u2013Marie\u2013Tooth type 2B mutant Rab7 led to prolonged mitochondria\u2013lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis\u2013mediated contact site untethering. We further generated a Charcot\u2013Marie\u2013Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria\u2013lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria\u2013lysosome contact sites in the pathogenesis of peripheral neuropathy.<\/jats:p>","DOI":"10.1073\/pnas.2313010120","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T14:02:48Z","timestamp":1698242568000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":26,"title":["Misregulation of mitochondria\u2013lysosome contact dynamics in Charcot\u2013Marie\u2013Tooth Type 2B disease Rab7 mutant sensory peripheral neurons"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3188-4342","authenticated-orcid":false,"given":"Yvette C.","family":"Wong","sequence":"first","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirupa D.","family":"Jayaraj","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tayler B.","family":"Belton","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-0570","authenticated-orcid":false,"given":"George C.","family":"Shum","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2804-2387","authenticated-orcid":false,"given":"Hannah E.","family":"Ball","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjun","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0801-8267","authenticated-orcid":false,"given":"Abigail L. D.","family":"Tadenev","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-1886","authenticated-orcid":false,"given":"Dimitri","family":"Krainc","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"},{"name":"Simpson Querrey Center for Neurogenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9229-3407","authenticated-orcid":false,"given":"Robert W.","family":"Burgess","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela M.","family":"Menichella","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"},{"name":"Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,10,25]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000373"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.2174\/1566524014666141010154205"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/367847"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20281"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000240068.21499.f5"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2013.10.023"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1529-8027.2012.00415.x"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9041028"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3677-07.2008"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp567"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4322-12.2013"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25486"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2019.02.004"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.01.005"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101262"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2019.05.033"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202206140"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.06.007"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.07.070"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.111633"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.111211"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.01612"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01096.2012"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2016.01.008"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2006.12.003"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-10-42"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92117"},{"key":"e_1_3_4_28_2","first-page":"853","article-title":"Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q","volume":"57","author":"Kwon J. M.","year":"1995","unstructured":"J. M. Kwon , Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum. Genet. 57, 853\u2013858 (1995).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22369"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep40620"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12557"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01503-6"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201802166"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2016003772"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22113-3"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.030"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.8.2245"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.624823"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1341"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00782"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.858286"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07534"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16411-5"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.512"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.509"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.508"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa243"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105300"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03632-1"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012419-032711"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2020.03.009"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2006.09.003"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.10.010"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2012.04.001"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm314"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq082"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1111\/jns5.12066"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167573"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao1785"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124194"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3356"},{"key":"e_1_3_4_62_2","doi-asserted-by":"crossref","unstructured":"Y. Yamada A SARM1\/mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model. J. Clin. Invest. 132 e161566 (2022). e161566","DOI":"10.1172\/JCI161566"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.00263"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9861(20001120)427:3<340::AID-CNE2>3.0.CO;2-Y"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2009.11.002"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.irn.2019.05.002"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.417766"},{"key":"e_1_3_4_68_2","first-page":"930","article-title":"Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B","volume":"14","author":"Colecchia D.","year":"2018","unstructured":"D. Colecchia , Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B. Autophagy 14, 930\u2013941 (2018).","journal-title":"Autophagy"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-020-03510-1"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.258559"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2003236117"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12152-2"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.784880"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.04.020"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adh3347"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2313010120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T14:03:11Z","timestamp":1698242591000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2313010120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,25]]},"references-count":75,"journal-issue":{"issue":"44","published-print":{"date-parts":[[2023,10,31]]}},"alternative-id":["10.1073\/pnas.2313010120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2313010120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,25]]},"assertion":[{"value":"2023-08-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2313010120"}}