| First Author | Bustos V | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 27 | Pages | 7148-7153 |
| PubMed ID | 28533369 | Mgi Jnum | J:244669 |
| Mgi Id | MGI:5913448 | Doi | 10.1073/pnas.1705240114 |
| Citation | Bustos V, et al. (2017) Phosphorylated Presenilin 1 decreases beta-amyloid by facilitating autophagosome-lysosome fusion. Proc Natl Acad Sci U S A 114(27):7148-7153 |
| abstractText | Presenilin 1 (PS1), the catalytic subunit of the gamma-secretase complex, cleaves betaCTF to produce Abeta. We have shown that PS1 regulates Abeta levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the gamma-secretase complex, selective phosphorylation of PS1 on Ser367 decreases Abeta levels by increasing betaCTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates betaCTF degradation. We show that PS1 phosphorylated at Ser367, but not nonphosphorylated PS1, interacts with Annexin A2, which, in turn, interacts with the lysosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8. Annexin A2 facilitates the binding of Vamp8 to the autophagosomal SNARE Syntaxin 17 to modulate the fusion of autophagosomes with lysosomes. Thus, PS1 phosphorylated at Ser367 has an antiamyloidogenic function, promoting autophagosome-lysosome fusion and increasing betaCTF degradation. Drugs designed to increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer's disease. |
