Presenilin-1 regulates the expression of p62 to Govern p62-dependent Tau degradation
- Authors
- Tung, Y.T., Wang, B.J., Hsu, W.M., Hu, M.K., Her, G.M., Huang, W.P., and Liao, Y.F.
- ID
- ZDB-PUB-140410-2
- 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.