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Restricted Location of PSEN2/?-Secretase Determines Substrate Specificity and Generates an Intracellular A? Pool.


ABSTRACT: ?-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing ?-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this ?-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex. Accordingly, PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular A? that contains longer A?; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer A? further. Moreover, a subset of FAD mutants in PSEN1, normally more broadly distributed in the cell, phenocopies PSEN2 and shifts its localization to late endosomes/lysosomes. Thus, localization of ?-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone A?42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis.

SUBMITTER: Sannerud R 

PROVIDER: S-EPMC7439524 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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γ-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing γ-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex. Accordingly, PSEN2 selectively  ...[more]

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