OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin

Jonghee Han, Sunmin Jung, Jiyeon Jang, Tae In Kam, Hyunwoo Choi, Byung Ju Kim, Jihoon Nah, Dong Gyu Jo, Toshiyuki Nakagawa, Masaki Nishimura, Yong Keun Jung

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2561-2576
Number of pages16
JournalCellular and Molecular Life Sciences
Volume71
Issue number13
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Nicastrin
  • OCIAD2
  • γ-secretase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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