ZFIN ID: ZDB-PUB-140410-2
Presenilin-1 regulates the expression of p62 to Govern p62-dependent Tau degradation
Tung, Y.T., Wang, B.J., Hsu, W.M., Hu, M.K., Her, G.M., Huang, W.P., and Liao, Y.F.
Date: 2014
Source: Molecular neurobiology   49(1): 10-27 (Journal)
Registered Authors: Her, Guor Muor
Keywords: none
MeSH Terms:
  • Adaptor Proteins, Signal Transducing/biosynthesis
  • Adaptor Proteins, Signal Transducing/genetics
  • Adaptor Proteins, Signal Transducing/physiology*
  • Animals
  • Cell Line, Tumor
  • Down-Regulation/genetics
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Mutation
  • Phenotype
  • Presenilin-1/deficiency
  • Presenilin-1/genetics
  • Presenilin-1/physiology*
  • Proteolysis*
  • Zebrafish/genetics
  • tau Proteins/antagonists & inhibitors*
  • tau Proteins/genetics
  • tau Proteins/metabolism*
PubMed: 23794287 Full text @ Mol. Neurobiol.

Mutations in presenilin-1 (PS1) are tightly associated with early-onset familial Alzheimer’s disease (FAD), which is characterized by extracellular amyloid plaques and the accumulation of intracellular Tau. In addition to being the catalytic subunit of γ-secretase, PS1 has been shown to regulate diverse cellular functions independent of its proteolytic activity. We found that cells deficient in PS1 exhibit reduced levels of p62 protein, a cargo-receptor shuttling Tau for degradation. The downregulation of PS1 led to a significant decrease in both the protein and mRNA transcript of p62, concomitant with attenuated p62 promoter activity. This PS1-dependent regulation of p62 expression was mediated through an Akt/AP-1 pathway independent of the proteolytic activity of PS1/γ-secretase. This p62-mediated Tau degradation was significantly impaired in PS1-deficient cells, which can be rescued by ectopic expression of either p62 or wild-type PS1 but not mutant PS1 containing FAD-linked mutations. Our study suggests a novel function for PS1 in modulating p62 expression to control the proteostasis of Tau.