Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion
Abstract
Autophagy is a catabolic process involving the formation of double-membrane–bound organelles called autophagosomes, which participate in the degradation of intracellular material through fusion with lysosomes. We have found a level of regulation of autophagosomal–lysosomal fusion where Presenilin 1 (PS1) phosphorylated at Ser367 specifically binds Annexin A2, which, through successive binding steps, facilitates this fusion. Lack of phosphorylation on PS1 1 Ser367 causes accumulation of partially fused autophagosomes and lysosomes in mouse brain and reduced autophagic flux. This inhibition of autophagy leads to decreased βCTF degradation and accumulation of toxic Aβ-peptide in the brain. This signaling pathway offers new potential drug targets for Alzheimer’s disease.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 22, 2017
- Source ID
- 10.1073/pnas.1705240114
Entities
People
- Alison Lam
- Ashley Bispo
- Fred S. Gorelick
- Marc Flajolet
- Maria V. Pulina
- Paul Greengard
- Victor Bustos
Organizations
- Fisher Center for Alzheimer's Research Foundation
- Freedom Together Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institutes of Health
- The Rockefeller University
- United States Department of Defense
- Yale University