Details

Autor(en) / Beteiligte

• Han, Jonghee
• Jung, Sunmin
• Jang, Jiyeon
• Kam, Tae-in
• Choi, Hyunwoo
• Kim, Byung-ju
• Nah, Jihoon
• Jo, Dong-gyu
• Nakagawa, Toshiyuki
• Nishimura, Masaki
• Jung, Yong-keun

Titel

OCIAD2 activates [gamma]-secretase to enhance amyloid [beta] production by interacting with nicastrin

Ist Teil von

• Cellular and molecular life sciences : CMLS, 2014-07, Vol.71 (13), p.2561

Ort / Verlag

Basel: Springer Nature B.V

Erscheinungsjahr

2014

Link zum Volltext

Quelle

SpringerLink

Beschreibungen/Notizen

• The gamma (γ)-secretase holoenzyme is composed of four core proteins and cleaves APP to generate amyloid beta (A[beta]), a key molecule that causes major neurotoxicity during the early stage of Alzheimer's disease (AD). However, despite its important role in A[beta] production, little is known about the regulation of γ-secretase. OCIAD2, a novel modulator of γ-secretase that stimulates A[beta] production, and which was isolated from a genome-wide functional screen using cell-based assays and a cDNA library comprising 6,178 genes. Ectopic expression of OCIAD2 enhanced A[beta] production, while reduction of OCIAD2 expression suppressed it. OCIAD2 expression facilitated the formation of an active γ-secretase complex and enhanced subcellular localization of the enzyme components to lipid rafts. OCIAD2 interacted with nicastrin to stimulate γ-secretase activity. OCIAD2 also increased the interaction of nicastrin with C99 and stimulated APP processing via γ-secretase activation, but did not affect Notch processing. In addition, a cell-permeable Tat-OCIAD2 peptide that interfered with the interaction of OCIAD2 with nicastrin interrupted the γ-secretase-mediated AICD production. Finally, OCIAD2 expression was significantly elevated in the brain of AD patients and PDAPP mice. This study identifies OCIAD2 as a selective activator of γ-secretase to increase A[beta] generation.[PUBLICATION ABSTRACT]