Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion

2017/05/22 by Victor Bustos, Maria V. Pulina, Ashley Bispo +5 · 25 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Cellular transport and secretion #Alzheimer's disease research and treatments #Autophagy in Disease and Therapy

paper · pdf · doi:10.1073/pnas.1705240114

Abstract

Significance 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.

Citations

• Bidirectional regulation of Aβ levels by Presenilin 1

Cited by

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• Recent Insights Into the Pathogenic Mechanism of Pancreatitis: Role of Acinar Cell Organelle Disorders. [europepmc]
• Recent progress in the role of autophagy in neurological diseases. [europepmc]
• Exploring the bi-directional relationship between autophagy and Alzheimer's disease. [europepmc]
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• Presenilin 1 Regulates Membrane Homeostatic Pathways that are Dysregulated in Alzheimer's Disease. [europepmc]
• Lack of a site-specific phosphorylation of Presenilin 1 disrupts microglial gene networks and progenitors during development. [europepmc]
• The autophagy research in electron microscopy. [europepmc]
• Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance. [europepmc]
• Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 . [europepmc]
• Annexin Animal Models-From Fundamental Principles to Translational Research. [europepmc]
• Role of SNAREs in Neurodegenerative Diseases. [europepmc]
• Long-term running exercise alleviates cognitive dysfunction in APP/PSEN1 transgenic mice via enhancing brain lysosomal function. [europepmc]
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• The protein kinase CK1: Inhibition, activation, and possible allosteric modulation. [europepmc]
• Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2 -dependent manner in mice. [europepmc]
• Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism. [europepmc]
• Human amygdala involvement in Alzheimer's disease revealed by stereological and dia-PASEF analysis. [europepmc]
• Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer. [europepmc]

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