[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-513317-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-513317-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","presenilin-2-interacts-with-lamtor1-at-late-endosomelysosome-endoplasmic-reticulum-contact-sites-abstract","Presenilin-2 interacts with Lamtor1 at late endosome/lysosome-endoplasmic reticulum contact sites - Abstract","","Mutations in Presenilin-2 (PSEN2), a catalytic subunit of the γ-secretase complex, cause familial Alzheimer’s disease. Beyond β-amyloid generation, the work tests whether PSEN2 supports essential cellular functions affecting neuronal vulnerability. PSEN2 in late endosomes/lysosomes localizes at endoplasmic reticulum contact sites. Proximity-based biotinylation maps its local interactome and reveals a novel Lamtor1 interaction, linking altered PSEN2 expression to disrupted Lamtor1-dependent signaling, BORC recruitment, and changes in mTORC1 activity, validated in mouse hippocampal neurons.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/presenilin-2-interacts-with-lamtor1-at-late-endosomelysosome-endoplasmic-reticulum-contact-sites-abstract/513317/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/presenilin-2-interacts-with-lamtor1-at-late-endosomelysosome-endoplasmic-reticulum-contact-sites-abstract/513317.png","ImageObject",300,407,{"name":42,"@type":43},"Connor ","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-01","2026-10-06",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",7,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is the main biological question about PSEN2 in this study?","Question",{"text":63,"@type":64},"The study asks whether PSEN2 performs key cellular functions beyond generating β-amyloid, and whether disruption of those functions could contribute to neuronal vulnerability in early Alzheimer’s disease.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Where does PSEN2 localize according to the findings?",{"text":68,"@type":64},"PSEN2 in late endosomes/lysosomes localizes specifically at contact sites with the endoplasmic reticulum, implicating PSEN2 in inter-organellar communication.",{"name":70,"@type":61,"acceptedAnswer":71},"What interaction and downstream effects are linked to PSEN2?",{"text":72,"@type":64},"Using proximity-dependent biotinylation with APEX2-tagged PSEN2, the study identifies a novel interaction with Lamtor1 at LE/Lys-ER contacts; altered PSEN2 expression disrupts Lamtor1-dependent signaling, promotes BORC recruitment, and affects nutrient-dependent mTORC1 activity.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},513317,1791367950,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,109,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":107,"slug":108},40,"healthcare",{"id":110,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},8,"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":55,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},687207022233,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","VIB-KU Leuven Center for Brain & Disease Research [https://orcid.org/0000-0003-0150-9661](https://orcid.org/0000-0003-0150-9661)  \nVIB and KU Leuven [https://orcid.org/0000-0003-2594-9020](https://orcid.org/0000-0003-2594-9020)  \nKU Leuven & VIB [https://orcid.org/0000-0002-6694-3154](https://orcid.org/0000-0002-6694-3154)  \nVIB-KU Leuven Center for Brain & Disease Research  \nVIB-KU Leuven Center for Brain & Disease Research  \nVIB-KU Leuven Center for Brain & Disease Research  \nVIB-KU Leuven Center for Brain & Disease Research  \nVIB-KU Leuven [https://orcid.org/0000-0003-1](https://orcid.org/0000-0003-1)176-7277  \nVIB-KU Leuven Center for Brain & Disease Research  \nVIB&UAntwerp  \nKU Leuven & VIB [https://orcid.org/0000-0002-6073-1679](https://orcid.org/0000-0002-6073-1679)  \nVIB-KU Leuven Center for Brain & Disease Research  \nVIB&UGent  \nNovember 12th, 2025  \n [https://doi.org/10.21203/rs.3.rs-8068059/v1](https://doi.org/10.21203/rs.3.rs-8068059/v1)  \n 􀁱 􀅏 This work is licensed under a Creative Commons Attribution 4.0 International License.  \nRead Full License  \n There is  Competing Interest.  \nPresenilin-2 interacts with Lamtor1 at late endosome/lysosome-endoplasmic reticulum contact sites  \nto guard endolysosomal homeostasis  \nCéline Vrancx 1,2, Ragna Sannerud 1,2*, Rosanne Wouters 1,2*, Iván Ramos Calvo 1,2*, Anika Perdok 1,2§, Rosanna Poll 1,2, Nikky Corthout3, Xiaojuan Yang 1,2§, Ruben Hellemans 1,2§§, Inge Vorsters1,2, Kristel Vennekens 1,2, Francis Impens4,5,6, Wim Annaert 1,2\\#  \n1Laboratory for Membrane Trafficking, VIB Center for Brain & Disease Research, Leuven, Belgium 2Department of Neurosciences, KU Leuven, Leuven, Belgium  \n3 VIB BioImaging Core, VIB-Center for Brain and Disease Research, Leuven, 3000, Belgium. 4 VIB-UGent Center for Medical Biotechnology, Ghent, Belgium  \n5 VIB Proteomics Core, Ghent, Belgium  \n6Department of Biomolecular Medicine, Ghent University, Ghent, Belgium  \n*Equal contributors  \n§Current address: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA  \n§§Current address: VIB Center for Molecular Neurology, Antwerp, Belgium  \nDepartment of Biomedical Sciences, University ofAntwerp, Antwerp, Belgium  \n\\#Corresponding author: Wim Annaert, [wim.annaert@kuleuven.be](wim.annaert@kuleuven.be)  \nAbstract  \nMutations in Presenilin-2 (PSEN2), a catalytic subunit of the γ-secretase complex, cause familial Alzheimer’s disease (AD) . Beyond its role in β-amyloid generation, we hypothesized that PSEN2 also supports key cellular functions whose disruption may underlie neuronal vulnerability. We now demonstrate that PSEN2 in late endosomes/lysosomes (LE/Lys) specifically localizes at contact sites with the endoplasmic reticulum (ER), implicating it in inter-organellar communication. Using proximity-dependent biotinylation of APEX2-tagged PSEN2, we defined its local interactome and identified a novel interaction with Lamtor1 –a regulator of vesicle trafficking and mTORC1 signaling– within LE/Lys-ER contacts. Mechanistically, altered PSEN2 expression disrupted Lamtor1-dependent signaling, promoting the recruitment of the BORC complex at LE/Lys, thereby driving their repositioning, while also affecting nutrient-dependent mTORC1 activity. These findings are recapitulated in mouse hippocampal neurons, uncovering a novel role for PSEN2 in maintaining organelle homeostasis with relevance to early events in AD pathogenesis.  \nIntroduction  \nThe tetrameric γ-secretase complex is central to the pathogenesis of Alzheimer’s disease (AD), since its enzymatic activity is required to cleave the Amyloid Precursor Protein (APP) C-terminal fragments (APPCTFs) and generate the well-known β-amyloid peptides 1,2, which can toxically aggregate in the brain and induce synaptic and neuronal loss3. Notably, mutations in the presenilin-1 (PSEN1) and presenilin-2  \n(PSEN2) genes, which encode the catalytic subunit of γ-secretase, as well as in the APP gene, cause earlyonset famil","cbCaip9HtyhEENwP","https://ap.wps.com/l/cbCaip9HtyhEENwP","pdf",2793931,46,"English","# Abstract\n# Introduction","[{\"question\":\"What is the main biological question about PSEN2 in this study?\",\"answer\":\"The study asks whether PSEN2 performs key cellular functions beyond generating β-amyloid, and whether disruption of those functions could contribute to neuronal vulnerability in early Alzheimer’s disease.\"},{\"question\":\"Where does PSEN2 localize according to the findings?\",\"answer\":\"PSEN2 in late endosomes/lysosomes localizes specifically at contact sites with the endoplasmic reticulum, implicating PSEN2 in inter-organellar communication.\"},{\"question\":\"What interaction and downstream effects are linked to PSEN2?\",\"answer\":\"Using proximity-dependent biotinylation with APEX2-tagged PSEN2, the study identifies a novel interaction with Lamtor1 at LE/Lys-ER contacts; altered PSEN2 expression disrupts Lamtor1-dependent signaling, promotes BORC recruitment, and affects nutrient-dependent mTORC1 activity.\"}]","Presenilin-2 interacts with Lamtor1 at late endosome/lysosome-endoplasmic reticulum contact sites - Abstract | PDF",1791283273,116]