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 journalArticle

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 - Jan 1 2014
Externally publishedYes

Fingerprint

Amyloid Precursor Protein Secretases
Amyloid
Alzheimer Disease
Holoenzymes
Brain Diseases
Gene Library
Genome
Lipids
Peptides
Enzymes

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

In: Cellular and Molecular Life Sciences, Vol. 71, No. 13, 01.01.2014, p. 2561-2576.

Research output: Contribution to journalArticle

Han, J, Jung, S, Jang, J, Kam, T-I, Choi, H, Kim, BJ, Nah, J, Jo, DG, Nakagawa, T, Nishimura, M & Jung, YK 2014, 'OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin', Cellular and Molecular Life Sciences, vol. 71, no. 13, pp. 2561-2576. https://doi.org/10.1007/s00018-013-1515-x
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. / OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin. In: Cellular and Molecular Life Sciences. 2014 ; Vol. 71, No. 13. pp. 2561-2576.
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