Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway

Jin Chu, Jian Guo Li, Nicholas E. Hoffman, Madesh Muniswamy, Domenico Praticò

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

A major hallmark feature of Alzheimer's disease is the accumulation of amyloid β (Aβ), whose formation is regulated by the γ-secretase complex and its activating protein (also known as γ-secretase activating protein, or GSAP). Because GSAP interacts with the γ-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. GSAP derives from a C-terminal fragment of a larger precursor protein of 98 kDa via a caspase 3-mediated cleavage. However, the mechanism(s) involved in its degradation remain unknown. In this study, we show that GSAP has a short half-life of approximately 5 h. Neuronal cells treated with proteasome inhibitors markedly prevented GSAP protein degradation, which was associated with a significant increment in Aβ levels and γ-secretase cleavage products. In contrast, treatment with calpain blocker and lysosome inhibitors had no effect. In addition, we provide experimental evidence that GSAP is ubiquitinated. Taken together, our findings reveal that GSAP is degraded through the ubiquitin-proteasome system. Modulation of the GSAP degradation pathway may be implemented as a viable target for a safer anti-Aβ therapeutic approach in Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)432-439
Number of pages8
JournalJournal of Neurochemistry
Volume133
Issue number3
DOIs
StatePublished - May 1 2015
Externally publishedYes

Fingerprint

Amyloid Precursor Protein Secretases
Proteasome Endopeptidase Complex
Ubiquitin
Degradation
Alzheimer Disease
Proteins
Proteasome Inhibitors
Calpain
Protein Precursors
Lysosomes
Amyloid
Caspase 3
Proteolysis
Half-Life
Modulation
Therapeutics

Keywords

  • Alzheimer's disease
  • amyloid β
  • APP
  • protein degradation
  • γ-secretase activating protein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway. / Chu, Jin; Li, Jian Guo; Hoffman, Nicholas E.; Muniswamy, Madesh; Praticò, Domenico.

In: Journal of Neurochemistry, Vol. 133, No. 3, 01.05.2015, p. 432-439.

Research output: Contribution to journalArticle

Chu, Jin ; Li, Jian Guo ; Hoffman, Nicholas E. ; Muniswamy, Madesh ; Praticò, Domenico. / Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway. In: Journal of Neurochemistry. 2015 ; Vol. 133, No. 3. pp. 432-439.
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