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However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of\n                    <jats:italic>Plekhg5<\/jats:italic>\n                    in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1\n                    <jats:sup>G93A<\/jats:sup>\n                    following deletion of\n                    <jats:italic>Plekhg5<\/jats:italic>\n                    in SOD1\n                    <jats:sup>G93A<\/jats:sup>\n                    mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-52875-5","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T15:01:43Z","timestamp":1728054103000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy"],"prefix":"10.1038","volume":"15","author":[{"given":"Amy-Jayne","family":"Hutchings","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bita","family":"Hambrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4558-1329","authenticated-orcid":false,"given":"Alexander","family":"Veh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6544-4102","authenticated-orcid":false,"given":"Neha Jadhav","family":"Giridhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2548-9191","authenticated-orcid":false,"given":"Abdolhossein","family":"Zare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Angerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorben","family":"Ohnesorge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5649-591X","authenticated-orcid":false,"given":"Maren","family":"Schenke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhuvaneish T.","family":"Selvaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6827-1593","authenticated-orcid":false,"given":"Siddharthan","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Sterneckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Petri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-2841","authenticated-orcid":false,"given":"Bettina","family":"Seeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7137-8260","authenticated-orcid":false,"given":"Michael","family":"Briese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6941-2669","authenticated-orcid":false,"given":"Christian","family":"Stigloher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9288-9481","authenticated-orcid":false,"given":"Thorsten","family":"Bischler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-7791","authenticated-orcid":false,"given":"Andreas","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9699-9351","authenticated-orcid":false,"given":"Markus","family":"Damme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4737-2974","authenticated-orcid":false,"given":"Michael","family":"Sendtner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-6554","authenticated-orcid":false,"given":"Patrick","family":"L\u00fcningschr\u00f6r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,4]]},"reference":[{"key":"52875_CR1","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nature04723","volume":"441","author":"M Komatsu","year":"2006","unstructured":"Komatsu, M. et al. 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