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P3–072: Gamma‐secretase trims ε‐cleaved products to beta‐amyloid 40 and beta‐amyloid 42 via two main pathways
Author(s) -
Fernandez Marty,
Wolfe Michael
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1142
Subject(s) - cleavage (geology) , amyloid precursor protein secretase , amyloid precursor protein , chemistry , enzyme , alpha secretase , protein precursor , in vitro , biochemistry , trimming , amyloid beta , pathogenesis , biology , alzheimer's disease , peptide , disease , medicine , immunology , computer science , paleontology , fracture (geology) , operating system
characterizes AD.Methods: PS1/2 and mitofusin 1 and 2 (Mfn1/2), the two major ER-mitochondria tethers, knock out (KO) MEFs were used for studying FAD-PS2 over-expression (or wt PS2 down-regulation by specific siRNA) effects on ER-mitochondria cross-talk, evaluating: (i) ER-mitochondria interactions, in cells co-expressing also two GFP variants differentially localized in the two organelles; (ii) Ca 2+ shuttling between ER and mitochondria by employing genetically encoded Ca 2+ indicators specifically localized to the cytosol or mitochondria.Classical biochemical approaches were also used to check PS2 molecular interaction with Mfn1/2, and its selective MAM localization. Results: We found that PS2 and Mfn2 need each other to exert their tethering function (while Mfn1 is dispensable). IP experiments demonstrated a direct interaction between the two proteins, both in cis and in trans, mediated by a specific PS2 domain. Finally, in FAD-PS2 transgenic mice brain, mutated PS2 results more strongly enriched in MAMs compared to the wt protein. Conclusions: PS2 influences ER-mitochondria juxtaposition by physically interacting with Mfn2. The two proteins co-operate to exert their tether function. PS2-FAD mutants, being more enriched in MAMs than the wt protein, are likely more prone to bind/stabilize Mfn2 homotypic complexes in these domains, leading to an altered ER-mitochondria interplay that could contribute to AD.