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Trans. R. Soc. B"],"published-print":{"date-parts":[[2024,4,8]]},"abstract":"<jats:p>\n                    The endosomal gene\n                    <jats:italic>SORL1<\/jats:italic>\n                    is a strong Alzheimer's disease (AD) risk gene that harbours loss-of-function variants causative for developing AD. The\n                    <jats:italic>SORL1<\/jats:italic>\n                    protein SORL1\/SORLA is an endosomal receptor that interacts with the multi-protein sorting complex retromer to traffic various cargo through the endo-lysosomal network (ELN). Impairments in endo-lysosomal trafficking are an early cellular symptom in AD and a novel therapeutic target. However, the cell types of the central nervous system are diverse and use the ELN differently. If this pathway is to be effectively therapeutically targeted, understanding how key molecules in the ELN function in various cell types and how manipulating them affects cell-type specific responses relative to AD is essential. Here, we discuss an example where deficiency of SORL1 expression in a human model leads to stress on early endosomes and recycling endosomes in neurons, but preferentially leads to stress on lysosomes in microglia. The differences observed in these organelles could relate to the unique roles of these cells in the brain as neurons are professional secretory cells and microglia are professional phagocytic cells. Experiments to untangle these differences are fundamental to advancing the understanding of cell biology in AD and elucidating important pathways for therapeutic development. Human-induced pluripotent stem cell models are a valuable platform for such experiments.\n                  <\/jats:p>\n                  <jats:p>This article is part of a discussion meeting issue \u2018Understanding the endo-lysosomal network in neurodegeneration\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2022.0389","type":"journal-article","created":{"date-parts":[[2024,2,18]],"date-time":"2024-02-18T19:05:18Z","timestamp":1708283118000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Differential effects of\n                    <i>SORL1<\/i>\n                    deficiency on the endo-lysosomal network in human neurons and microglia"],"prefix":"10.1098","volume":"379","author":[{"given":"Swati","family":"Mishra","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98109, USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Jayadev","sequence":"additional","affiliation":[{"name":"Deparment of Neurology, University of Washington, Seattle, WA 98109, USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-0339","authenticated-orcid":true,"given":"Jessica E.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98109, USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2024,2,19]]},"reference":[{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700359"},{"key":"e_1_3_7_3_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-16-06142.1997"},{"key":"e_1_3_7_4_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-01-00186.1996"},{"key":"e_1_3_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2004.02.027"},{"key":"e_1_3_7_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64538-5"},{"key":"e_1_3_7_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1993.tb18291.x"},{"key":"e_1_3_7_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/64.2.113"},{"key":"e_1_3_7_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1596489"},{"key":"e_1_3_7_10_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0556-12.2012"},{"key":"e_1_3_7_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.020"},{"key":"e_1_3_7_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.05.008"},{"key":"e_1_3_7_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.07.050"},{"key":"e_1_3_7_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj5716"},{"key":"e_1_3_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.07.010"},{"key":"e_1_3_7_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0161969"},{"key":"e_1_3_7_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01084-8"},{"key":"e_1_3_7_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-022-00547-7"},{"key":"e_1_3_7_19_2","unstructured":"Bellenguez CEA. 2020 New insights on the genetic etiology of Alzheimer's and related dementia. medRxiv. 2020. 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