Journal
MOLECULAR NEUROBIOLOGY
Volume 49, Issue 1, Pages 10-27Publisher
SPRINGER
DOI: 10.1007/s12035-013-8482-y
Keywords
Presenilin; p62; Tau; Alzheimer's disease; Autophagy; gamma-Secretase
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Funding
- National Science Council, Taiwan [NSC 98-2311-B-002-004-MY3, NSC 98-2320-B-001-014-MY2]
- Academia Sinica
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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 gamma-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/gamma-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.
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