OCIAD2 activates gamma-secretase to enhance amyloid beta production by interacting with nicastrin
- Authors
- Han, J[Han, Jonghee]; Jung, S[Jung, Sunmin]; Jang, J[Jang, Jiyeon]; Kam, TI[Kam, Tae-In]; Choi, H[Choi, Hyunwoo]; Kim, BJ[Kim, Byung-Ju]; Nah, J[Nah, Jihoon]; Jo, DG[Jo, Dong-Gyu]; Nakagawa, T[Nakagawa, Toshiyuki]; Nishimura, M[Nishimura, Masaki]; Jung, YK[Jung, Yong-Keun]
- Issue Date
- Jul-2014
- Publisher
- SPRINGER BASEL AG
- Keywords
- Alzheimer' s disease; OCIAD2; gamma-secretase; Nicastrin
- Citation
- CELLULAR AND MOLECULAR LIFE SCIENCES, v.71, no.13, pp.2561 - 2576
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELLULAR AND MOLECULAR LIFE SCIENCES
- Volume
- 71
- Number
- 13
- Start Page
- 2561
- End Page
- 2576
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/52509
- DOI
- 10.1007/s00018-013-1515-x
- ISSN
- 1420-682X
- Abstract
- The gamma (gamma)-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 gamma-secretase. OCIAD2, a novel modulator of gamma-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 gamma-secretase complex and enhanced subcellular localization of the enzyme components to lipid rafts. OCIAD2 interacted with nicastrin to stimulate gamma-secretase activity. OCIAD2 also increased the interaction of nicastrin with C99 and stimulated APP processing via gamma-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 gamma-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 gamma-secretase to increase A beta generation.
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