Presenilin-2 interacts with Lamtor1 at late endosome/lysosome-endoplasmic reticulum contact sites - Abstract

Oct 6, 2026

Uploaded by Connor

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.

LanguageEnglish

CategoryHealthcare

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Pages46

Reading Time1 h 56 min

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Abstract

Introduction

VIB-KU Leuven Center for Brain & Disease Research [https://orcid.org/0000-0003-0150-9661](https://orcid.org/0000-0003-0150-9661) VIB and KU Leuven [https://orcid.org/0000-0003-2594-9020](https://orcid.org/0000-0003-2594-9020) KU Leuven & VIB [https://orcid.org/0000-0002-6694-3154](https://orcid.org/0000-0002-6694-3154) VIB-KU Leuven Center for Brain & Disease Research VIB-KU Leuven Center for Brain & Disease Research VIB-KU Leuven Center for Brain & Disease Research VIB-KU Leuven Center for Brain & Disease Research VIB-KU Leuven [https://orcid.org/0000-0003-1](https://orcid.org/0000-0003-1)176-7277 VIB-KU Leuven Center for Brain & Disease Research VIB&UAntwerp KU Leuven & VIB [https://orcid.org/0000-0002-6073-1679](https://orcid.org/0000-0002-6073-1679) VIB-KU Leuven Center for Brain & Disease Research VIB&UGent November 12th, 2025 [https://doi.org/10.21203/rs.3.rs-8068059/v1](https://doi.org/10.21203/rs.3.rs-8068059/v1) 􀁱 􀅏 This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License There is Competing Interest. Presenilin-2 interacts with Lamtor1 at late endosome/lysosome-endoplasmic reticulum contact sites to guard endolysosomal homeostasis Céline 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\# 1Laboratory for Membrane Trafficking, VIB Center for Brain & Disease Research, Leuven, Belgium 2Department of Neurosciences, KU Leuven, Leuven, Belgium 3 VIB BioImaging Core, VIB-Center for Brain and Disease Research, Leuven, 3000, Belgium. 4 VIB-UGent Center for Medical Biotechnology, Ghent, Belgium 5 VIB Proteomics Core, Ghent, Belgium 6Department of Biomolecular Medicine, Ghent University, Ghent, Belgium *Equal contributors §Current address: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA §§Current address: VIB Center for Molecular Neurology, Antwerp, Belgium Department of Biomedical Sciences, University ofAntwerp, Antwerp, Belgium \#Corresponding author: Wim Annaert, [wim.annaert@kuleuven.be](wim.annaert@kuleuven.be) Abstract Mutations 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. Introduction The 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 (PSEN2) genes, which encode the catalytic subunit of γ-secretase, as well as in the APP gene, cause earlyonset famil

FAQs

What is the main biological question about PSEN2 in this study?

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.

Where does PSEN2 localize according to the findings?

PSEN2 in late endosomes/lysosomes localizes specifically at contact sites with the endoplasmic reticulum, implicating PSEN2 in inter-organellar communication.

What interaction and downstream effects are linked to PSEN2?

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.

Oct 6, 2026

Uploaded by Connor