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Project

Unraveling the unprecedented roles for Presenilin/?-secretase in inter-organellar membrane contact sites and how this modulates cellular calcium homeostasis

Mutations in presenilin (PSEN) 1 and 2 account for the majority cases of familial Alzheimer’s disease (FAD). Since their discovery, many teams have focused on how these mutations affect PSEN’s catalytic role in  producing toxic amyloid β peptides. Nevertheless, mutant PSENs have also been extensively linked to Ca2+ signaling pathways, for instance through storage compartments, like the endoplasmic reticulum (ER) and lysosomes. Ca2+ shuttling from these compartments is to a large extent organized through membrane contact sites (MCSs) with other organelles, e.g. ER-plasma membrane (PM) and ER-lysosome MCSs. How FAD-associated mutant PSENs modulate these MCSs is a largely uncharted territory. The host lab has demonstrated that PSEN1 and PSEN2 differ majorly in their sub-cellular locations, with PSEN1 broadly distributed at the PM and endosomes while PSEN2 is restricted to late endosomes/lysosomes (LE/Lys). Preliminary evidence from the host lab underscores that this distinct spatial distribution may reflect a selective involvement of the different PSENs in the compartment-specific Ca2+ handling. In this proposal, I will investigate the expression and function of the two PSENs at the respective MCSs, combining advanced biochemical and imaging strategies, unraveling their role in Ca2+ signaling through MCSs. I will extend this to FAD-associated mutations in PSENs, as this may provide novel mechanistic insights into the Ca2+ dysregulation observed in the patho-ethiology of AD.

Date:1 Oct 2022 →  Today
Keywords:Alzheimer’s disease and presenilins (PSEN1/2), membrane contact sites (MCSs) and Ca2+ handling, Single molecule localization microscopy (SMLM)
Disciplines:Intracellular compartments and transport, Proteins, Medical biochemistry and metabolism not elsewhere classified, Membrane structure and transport, Neurosciences not elsewhere classified