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- Title
OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin.
- Authors
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
- Abstract
The gamma (γ)-secretase holoenzyme is composed of four core proteins and cleaves APP to generate amyloid beta (Aβ), a key molecule that causes major neurotoxicity during the early stage of Alzheimer's disease (AD). However, despite its important role in Aβ production, little is known about the regulation of γ-secretase. OCIAD2, a novel modulator of γ-secretase that stimulates Aβ 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 Aβ 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 Aβ generation.
- Subjects
SECRETASES; AMYLOID beta-protein; NICASTRIN; ALZHEIMER'S disease; NEUROTOXICOLOGY; ANTISENSE DNA; NEUROBIOLOGY
- Publication
Cellular & Molecular Life Sciences, 2014, Vol 71, Issue 13, p2561
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-013-1515-x