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Loss of function variants in\n                    <jats:italic>SORL1<\/jats:italic>\n                    are causative for Alzheimer's disease (\n                    <jats:sc>AD<\/jats:sc>\n                    ) and decreased expression of SORLA has been repeatedly observed in human\n                    <jats:sc>AD<\/jats:sc>\n                    brains.\n                    <jats:italic>SORL1<\/jats:italic>\n                    is highly expressed in the central nervous system, including in microglia, the tissue\u2010resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC\u2010derived microglia\u2010like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to\n                    <jats:sc>AD<\/jats:sc>\n                    pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1\u201342 and synaptosomes is increased in SORLA\u2010deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired in\n                    <jats:italic>SORL1<\/jats:italic>\n                    \u2010deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in the proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo\u2010lysosomal network as a potential novel pathway through which\n                    <jats:italic>SORL1<\/jats:italic>\n                    may increase\n                    <jats:sc>AD<\/jats:sc>\n                    risk and contribute to the development of\n                    <jats:sc>AD<\/jats:sc>\n                    . Additionally, our findings may inform the development of novel lysosome and microglia\u2010associated drug targets for\n                    <jats:sc>AD<\/jats:sc>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/glia.70009","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T10:09:24Z","timestamp":1743847764000},"page":"1329-1348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Alzheimer's Disease Gene\n                    <i>SORL1<\/i>\n                    Regulates Lysosome Function in Human Microglia"],"prefix":"10.1002","volume":"73","author":[{"given":"Swati","family":"Mishra","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle Washington USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nader","family":"Morshed","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital, F.M. 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Kirby Neurobiology Center  Boston Massachusetts USA"},{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"},{"name":"Howard Hughes Medical Institute  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3164-9665","authenticated-orcid":false,"given":"Suman","family":"Jayadev","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington  Seattle Washington USA"},{"name":"Department of Neurology University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-0339","authenticated-orcid":false,"given":"Jessica E.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle Washington USA"},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2019.12.003"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1136(19990215)25:4<324::AID-GLIA2>3.0.CO;2-5"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13016"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/1759091417716610"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100740"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308558101"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(00)01794-3"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20106934\u20100_13"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200312055"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108882"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231810432"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm732"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4814-07.2008"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.10.016"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.06.005"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21072576"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.00628\u201013"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-01991-4"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167428"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.11.7003"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201806153"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166205"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.jnen.0000228205.19915.20"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010023\u201001558\u20102"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44318\u2010024\u201000177\u20103"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2012.10"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035\u2010024\u201000438\u20105"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13761"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2008.11.007"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2272-11.2012"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.7.2152"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2023.12.014"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M064089"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014\u20105793(96)01087\u20103"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ircmb.2015.07.008"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.87"},{"key":"e_1_2_11_38_1","doi-asserted-by":"crossref","unstructured":"Holstege H. 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