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

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

Resultado de la investigación: Articlerevisión exhaustiva

10 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)432-439
Número de páginas8
PublicaciónJournal of neurochemistry
Volumen133
N.º3
DOI
EstadoPublished - may. 1 2015
Publicado de forma externa

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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