{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:51:27Z","timestamp":1791197487798,"version":"4.1.0"},"reference-count":68,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,9,16]],"date-time":"2015-09-16T00:00:00Z","timestamp":1442361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS46616"],"award-info":[{"award-number":["NS46616"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ramzi Cotran Endowed Chair, Harvard Medical School"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Mutations in receptor expression enhancing protein 1 <jats:italic>(REEP1)<\/jats:italic> are associated with hereditary spastic paraplegias (HSPs). Although axonal degeneration is thought to be a predominant feature in HSP, the role of <jats:italic>REEP1<\/jats:italic> mutations in degeneration is largely unknown. Previous studies have implicated a role for REEP1 in the endoplasmic reticulum (ER), whereas others localized REEP1 with mitochondria. We sought to resolve the cellular localization of REEP1 and further elucidate the pathobiology underlying <jats:italic>REEP1<\/jats:italic> mutations in patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A combination of cellular imaging and biochemical approaches was used to refine the cellular localization of REEP1. Next, <jats:italic>Reep1<\/jats:italic> mutations associated with HSP were functionally tested in neuritic growth and degeneration assays using mouse cortical culture. Finally, a novel assay was developed and used with wild\u2010type and mutant <jats:italic>Reep1s<\/jats:italic> to measure the interactions between the ER and mitochondria.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that REEP1 is present at the ER\u2010mitochondria interface, and it contains subdomains for mitochondrial as well as ER localization. Knockdown of <jats:italic>Reep1<\/jats:italic> and expression of pathological <jats:italic>Reep1<\/jats:italic> mutations resulted in neuritic growth defects and degeneration. Finally, using our novel split\u2010<jats:italic>R<\/jats:italic>Luc8 assay, we show that REEP1 facilitates ER\u2010mitochondria interactions, a function diminished by disease\u2010associated mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our data potentially reconcile the current conflicting reports regarding REEP1 being either an ER or a mitochondrial protein. Furthermore, our results connect, for the first time, the disrupted ER\u2010mitochondria interactions to a failure in maintaining health of long axons in HSPs. Finally, the split\u2010<jats:italic>R<\/jats:italic>Luc8 assay offers a new tool to identify potential drugs for multiple neurodegenerative diseases with ER\u2010mitochondria interaction defects. Ann Neurol 2015;78:Ann Neurol 2015;78:679\u2013696<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24488","type":"journal-article","created":{"date-parts":[[2015,7,22]],"date-time":"2015-07-22T23:27:07Z","timestamp":1437607627000},"page":"679-696","source":"Crossref","is-referenced-by-count":99,"title":["Hereditary spastic paraplegia\u2010linked REEP1 modulates endoplasmic reticulum\/mitochondria contacts"],"prefix":"10.1002","volume":"78","author":[{"given":"Youngshin","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital Harvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Il\u2010Taeg","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital Harvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah J.","family":"Schoel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital Harvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginam","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital Harvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Golden","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women's Hospital Harvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,9,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-062111-150400"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrn2946","article-title":"Hereditary spastic paraplegias: membrane traffic and the motor pathway","volume":"12","author":"Blackstone C","year":"2010","journal-title":"Nat Rev Neurosci"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1386767"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1115-8"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40979"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65665"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.05.007"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076366"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.528687"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60560"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800986200"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/505361"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21542"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200303030-00038"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-008-0163-z"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI72324"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3440"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2008.12.002"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-386033-0.00002-5"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11910"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2013.2011"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1100735108"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.202"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.302794"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2507-13.2014"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt068"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr559"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01038-07"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzl023"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/ac0300800"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2010.05.003"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200604016"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017033108"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.86"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(02)00091-6"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2004.12.001"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1042\/AN20110031"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2014.01.017"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300677110"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.151"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2004.00587.x"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn026"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-9-71"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5469-08.2009"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-011-5934-z"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21480"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt644"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2013.12.008"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn026"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1207385"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07534"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009439"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2004.12.002"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.021"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4784-13.2014"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03254"},{"key":"e_1_2_8_58_1","first-page":"141","article-title":"Three\u2010dimensional distribution of smooth endoplasmic reticulum in myelinated axons","volume":"25","author":"Tsukita S","year":"1976","journal-title":"J Electron Microsc (Tokyo)"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.87.2.464"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.090219"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0618-11.2011"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4996"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.01.004"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4065-10.2011"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2012.04.001"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/syn.20602"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2010.03102.x"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-012-6723-z"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2013.139"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.24488","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.24488","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T01:34:53Z","timestamp":1696642493000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.24488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,16]]},"references-count":68,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,11]]}},"alternative-id":["10.1002\/ana.24488"],"URL":"https:\/\/doi.org\/10.1002\/ana.24488","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9,16]]}}}