Ferritin light chain interacts with PEN-2 and affects γ-secretase activity

Xinxin Li, Yiqian Liu, Qiuyang Zheng, Guorui Yao, Peng Cheng, Guojun D Bu, Huaxi Xu, Yun wu Zhang

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is primarily caused by overproduction/deposition of β-amyloid (Aβ) in the brain. Dysregulation of iron in the brain also contributes to AD. Although iron affects β-amyloid precursor protein (APP) expression and Aβ deposition, detailed role of iron in AD requires further elucidation. Aβ is produced by sequential proteolytic cleavages of APP by β-secretase and γ-secretase. The γ-secretase complex comprises presenilins (PS1 or PS2), nicastrin, APH-1, and PEN-2. Herein, we find that PEN-2 can interact with ferritin light chain (FTL), an important component of the iron storage protein ferritin. In addition, we show that overexpression of FTL increases the protein levels of PEN-2 and PS1 amino-terminal fragment (NTF) and promotes γ-secretase activity for more production of Aβ and notch intracellular domain (NICD). Furthermore, iron treatments increase the levels of FTL, PEN-2 and PS1 NTF and promote γ-secretase-mediated NICD production. Moreover, downregulation of FTL decreases the levels of PEN-2 and PS1 NTF. Together, our results suggest that iron can increase γ-secretase activity through promoting the level of FTL that interacts with and stabilizes PEN-2, providing a new molecular link between iron, PEN-2/γ-secretase and Aβ generation in AD.

Original languageEnglish (US)
Pages (from-to)90-94
Number of pages5
JournalNeuroscience Letters
Volume548
DOIs
StatePublished - Aug 26 2013
Externally publishedYes

Fingerprint

Apoferritins
Amyloid Precursor Protein Secretases
Iron
Alzheimer Disease
Presenilins
Serum Amyloid A Protein
Amyloid beta-Protein Precursor
Brain
Ferritins
Amyloid
Proteins
Down-Regulation

Keywords

  • γ-Secretase
  • Alzheimer's disease
  • Ferritin light chain
  • Iron
  • PEN-2

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ferritin light chain interacts with PEN-2 and affects γ-secretase activity. / Li, Xinxin; Liu, Yiqian; Zheng, Qiuyang; Yao, Guorui; Cheng, Peng; Bu, Guojun D; Xu, Huaxi; Zhang, Yun wu.

In: Neuroscience Letters, Vol. 548, 26.08.2013, p. 90-94.

Research output: Contribution to journalArticle

Li, Xinxin ; Liu, Yiqian ; Zheng, Qiuyang ; Yao, Guorui ; Cheng, Peng ; Bu, Guojun D ; Xu, Huaxi ; Zhang, Yun wu. / Ferritin light chain interacts with PEN-2 and affects γ-secretase activity. In: Neuroscience Letters. 2013 ; Vol. 548. pp. 90-94.
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AB - Alzheimer's disease (AD) is primarily caused by overproduction/deposition of β-amyloid (Aβ) in the brain. Dysregulation of iron in the brain also contributes to AD. Although iron affects β-amyloid precursor protein (APP) expression and Aβ deposition, detailed role of iron in AD requires further elucidation. Aβ is produced by sequential proteolytic cleavages of APP by β-secretase and γ-secretase. The γ-secretase complex comprises presenilins (PS1 or PS2), nicastrin, APH-1, and PEN-2. Herein, we find that PEN-2 can interact with ferritin light chain (FTL), an important component of the iron storage protein ferritin. In addition, we show that overexpression of FTL increases the protein levels of PEN-2 and PS1 amino-terminal fragment (NTF) and promotes γ-secretase activity for more production of Aβ and notch intracellular domain (NICD). Furthermore, iron treatments increase the levels of FTL, PEN-2 and PS1 NTF and promote γ-secretase-mediated NICD production. Moreover, downregulation of FTL decreases the levels of PEN-2 and PS1 NTF. Together, our results suggest that iron can increase γ-secretase activity through promoting the level of FTL that interacts with and stabilizes PEN-2, providing a new molecular link between iron, PEN-2/γ-secretase and Aβ generation in AD.

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