Abstract
γ-Secretase catalyzes intramembraneous proteolysis of several type I transmembrane proteins, including β-amyloid precursor protein (APP), to generate amyloid β protein (Aβ), a key player in the pathogenesis of Alzheimer's disease (AD). The critical components of the γ-secretase complex include presenilin (PS), nicastrin (NCT), presenilin enhancer-2 (PEN-2) and anterior pharynx defective-1 (APH-1). Abnormalities of the ubiquitin-proteasome pathway have been implicated in the pathogenesis of AD; while PS and PEN-2 turnover is regulated by this pathway, it is unknown whether the ubiquitin-proteasome pathway is also involved in the degradation of APH-1 protein. In this study, we found that the expression of endogenous and exogenous APH-1 significantly increased in cells treated with proteasome-specific inhibitors. The effect of the proteasome inhibitors on APH-1 was dose- and time-dependent. APH-1 protein was ubiquitinated. Pulse-chase metabolic labeling experiments showed that the degradation of newly synthesized radiolabeled APH-1 proteins was inhibited by lactacystin. Disruption of the PS1 and PS2 genes did not affect the degradation of APH-1 by the ubiquitin-proteasome pathway. Furthermore, over-expression of APH-1 and inhibition of proteasomal APH-1 degradation facilitated γ-secretase cleavage of APP to generate Aβ. These results demonstrate that the degradation of APH-1 protein is mediated by the ubiquitin-proteasome pathway.
Original language | English (US) |
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Pages (from-to) | 1403-1412 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 99 |
Issue number | 5 |
DOIs | |
State | Published - Dec 2006 |
Keywords
- Alzheimer's disease
- Anterior pharynx defective-1
- Proteasome
- Ubiquitin
- γ-secretase
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience