title: OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin.
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.
authors.affiliation: Creative Research Initiative (CRI)-Acceleration Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-747, Korea.
authors.forename: Jonghee
authors.initials: J
authors.lastname: Han
authors.forename: Sunmin
authors.initials: S
authors.lastname: Jung
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Jang
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Kam
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Choi
authors.forename: Byung-Ju
authors.initials: BJ
authors.lastname: Kim
authors.forename: Jihoon
authors.initials: J
authors.lastname: Nah
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D005347:Fibroblasts / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C576226:OCIAD2 protein, human; D051880:Receptors, Notch; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases