| First Author | Sannerud R | Year | 2016 |
| Journal | Cell | Volume | 166 |
| Issue | 1 | Pages | 193-208 |
| PubMed ID | 27293189 | Mgi Jnum | J:234652 |
| Mgi Id | MGI:5790534 | Doi | 10.1016/j.cell.2016.05.020 |
| Citation | Sannerud R, et al. (2016) Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular Abeta Pool. Cell 166(1):193-208 |
| abstractText | 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 Abeta that contains longer Abeta; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer Abeta 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 Abeta42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis. |
