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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,24]]},"abstract":"<jats:p>\n                    <jats:italic>SORL1<\/jats:italic>\n                    , the gene encoding the large multidomain SORLA protein, has emerged as only the fourth gene that when mutated can by itself cause Alzheimer\u2019s disease (AD), and as a gene reliably linked to both the early- and late-onset forms of the disease. SORLA is known to interact with the endosomal trafficking regulatory complex called retromer in regulating the recycling of endosomal cargo, including the amyloid precursor protein (APP) and the glutamate receptor GluA1. Nevertheless, SORLA\u2019s precise structural\u2013functional relationship in endosomal recycling tubules remains unknown. Here, we address these outstanding questions by relying on crystallographic and artificial-intelligence evidence to generate a structural model for how SORLA folds and fits into retromer-positive endosomal tubules, where it is found to dimerize via both SORLA\u2019s fibronectin-type-III (3Fn)- and VPS10p-domains. Moreover, we identify a SORLA fragment comprising the 3Fn-, transmembrane, and cytoplasmic domains that has the capacity to form a dimer, and to enhance retromer-dependent recycling of APP by decreasing its amyloidogenic processing. Collectively, these observations generate a model for how SORLA dimer (and possibly polymer) formation can function in stabilizing and enhancing retromer function at endosome tubules. These findings can inform investigation of the many AD-associated\n                    <jats:italic>SORL1<\/jats:italic>\n                    variants for evidence of pathogenicity and can guide discovery of novel drugs for the disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2212180120","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T13:49:27Z","timestamp":1674049767000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":35,"title":["Dimerization of the Alzheimer\u2019s disease pathogenic receptor SORLA regulates its association with retromer"],"prefix":"10.1073","volume":"120","author":[{"given":"Anne Mette G.","family":"Jensen","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Danish Research Institute of Translational Neuroscience, Aarhus University, Aarhus, 8000 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Kitago","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elnaz","family":"Fazeli","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Danish Research Institute of Translational Neuroscience, Aarhus University, Aarhus, 8000 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6573-146X","authenticated-orcid":false,"given":"Christian B.","family":"V\u00e6gter","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Danish Research Institute of Translational Neuroscience, Aarhus University, Aarhus, 8000 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Small","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University, New York, NY 10032"},{"name":"Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3668-3694","authenticated-orcid":false,"given":"Gregory A.","family":"Petsko","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4226-3354","authenticated-orcid":false,"given":"Olav M.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Danish Research Institute of Translational Neuroscience, Aarhus University, Aarhus, 8000 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0311-9"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00921-z"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"e_1_3_4_4_2","unstructured":"H. Holstege Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer\u2019s disease. Nat. Genet. 54 1786\u20131794 (2022)."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","unstructured":"P. Scheltens Alzheimer\u2019s disease. 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Christensen Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer\u2019s-associated protein sorLA. bioRxiv [Preprint] (2020) https:\/\/doi.org\/10.1101\/2020.07.12.199885 Accessed 1 August 2022.","DOI":"10.1101\/2020.07.12.199885"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-021-01294-4"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0053-7"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3896"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2017.08.003"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb1717"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2516"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-0043-1"},{"key":"e_1_3_4_24_2","article-title":"20 years anniversary for SORLA\/SORL1 (1996\u20132016)","volume":"4","author":"Monti G.","year":"2017","unstructured":"G. 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