Presenilin-2 interacts with Lamtor1 at late endosome/lysosome-endoplasmic reticulum contact sites to guard endolysosomal homeostasis
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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.
