期刊
CELL
卷 166, 期 1, 页码 193-208出版社
CELL PRESS
DOI: 10.1016/j.cell.2016.05.020
关键词
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资金
- VIB
- KU Leuven [C16/15/073, IDO/12/020]
- federal government [IAP P7/16]
- Hercules [AKUL/09/037, 11/30, 13/39]
- SAO [14017]
- Alzheimer's Association [IIRG-08-91535]
- NICHD Intramural Program [ZIA HD001607]
- IWT
- EU-ERC [208259]
- Fondation ARC [DOC20130606986, PJA20131200286]
- European Research Council (ERC) [208259] Funding Source: European Research Council (ERC)
gamma-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing gamma-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this gamma-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 beta that contains longer A beta; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer A beta 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 gamma-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone A beta 42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis.
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