Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Presenilin 2 (PSEN2)/γ-secretase localization differs from PSEN1, with PSEN2 restricted to late endosomes/lysosomes (LE/Lys).
• Distinct PSEN2 localization suggests roles beyond amyloid β production, including maintaining organellar homeostasis.
• Previous work linked impaired working memory and LTP to PSEN2's role in neuronal endolysosomal homeostasis.

Purpose of the Study:

• To investigate how altered PSEN2 expression molecularly affects LE/Lys functions and dynamics.
• To identify PSEN2 interactors involved in LE/Lys homeostasis.
• To elucidate the role of PSEN2 in neuronal organellar function and potential links to neurodegenerative diseases.

Main Methods:

• Utilized nonneuronal, primary hippocampal, and iPSC-derived human neurons with altered PSEN2 expression (deficiency or FAD mutation).
• Employed proximity-dependent biotinylation (APEX2 tagging) to identify the PSEN2 interactome within LE/Lys.
• Applied super-resolution microscopy and biochemical assays for validation and functional studies.

Main Results:

• Identified novel PSEN2 interactors linked to LE/Lys transport regulation and nutrient sensing.
• Revealed specific nano-domain organization of PSEN2 at the LE/Lys limiting membrane.
• Observed differential effects on axonal LE/Lys motility in PSEN2-deficient versus FAD-mutant PSEN2 neurons.

Conclusions:

• PSEN2/γ-secretase plays a significant role in regulating LE/Lys homeostasis.
• Findings provide new avenues for understanding early-stage Alzheimer's disease (AD) etiology related to endolysosomal dysfunction.
• Insights may also inform understanding of PSEN1 mutations, as some FAD mutations relocate PSEN1/γ-secretase to LE/Lys.