Author:

Keywords:

MANGO - 647458;info:eu-repo/grantAgreement/EC/H2020/647458, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, GAMMA-SECRETASE ACTIVITY, LYSOSOMAL MEMBRANE-PROTEINS, ALZHEIMERS-DISEASE, ENDOSOMAL DYSFUNCTION, AMYLOID ACCUMULATION, FORCE-FIELD, LOCALIZATION, PRESENILINS, MUTATIONS, MECHANISM, Adaptor Protein Complex 1, Alzheimer Disease, Amino Acid Motifs, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Animals, Cell Line, Tumor, Endosomes, Humans, Lysosomes, Mice, Peptide Fragments, Presenilin-1, Presenilin-2, Rats, Substrate Specificity, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

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 cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer Aβ 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 γ-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone Aβ42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis.