Project
Unraveling a novel role for PSEN2/?-secretase in late endosome/lysosome-endoplasmic reticulum contact sites: impact on Alzheimer’s disease pathogenesis
Presenilins (PSEN) 1 and 2 act as the catalytic core of γ-secretase and are responsible for the generation of β-amyloid (Aβ) peptides, of which aberrant accumulation is a key feature in Alzheimer’s disease (AD). The host lab demonstrated that the subcellular location of γ-secretase is defined by the PSEN homologue, with PSEN2 restricted to late endosomes and lysosomes (LE/Lys) and majorly contributing to the pool of intracellular toxic Aβ. Recent evidence of the lab confined PSEN2 to membrane contact sites (MCSs) of LE/Lys with the endoplasmic reticulum (ER). In-house interactomics identified an interaction of PSEN2 with an ER contact site protein and with nutrient sensing complexes, underscoring a yet unknown role for PSEN2 in inter-organellar communication between LE/Lys and ER. I will combine state-of-the-art super-resolution imaging and spatial interactomics to unravel the integral nano-environment of PSEN2 in LE/Lys-ER MCSs, with a particular attention to explore the functional connection with nutrient sensing and identify substrate involvement. These outcomes will be validated in iPSC-derived neurons and microglia, with a focus on how PSEN2 deficiency vs a familial AD causing mutation impact on endolysosomal homeostasis through modulating organellar communication, and this in both cell-autonomous and non-autonomous settings. These novel insights will provide a better understanding on the etiology of endolysosomal dysfunctions at early, preclinical stages of AD.