TY - JOUR
T1 - Ferritin light chain interacts with PEN-2 and affects γ-secretase activity
AU - Li, Xinxin
AU - Liu, Yiqian
AU - Zheng, Qiuyang
AU - Yao, Guorui
AU - Cheng, Peng
AU - Bu, Guojun
AU - Xu, Huaxi
AU - Zhang, Yun wu
N1 - Funding Information:
This study is supported by Grants from National Institutes of Health ( R01 AG038710 , R01 AG021173 , R01 NS046673 and R01 AG030197 ), the Alzheimer's Association, National Natural Science Foundation of China ( 30973150 , 81225008 and 81161120496 ), the Fundamental Research Funds for the Central Universities of China , and Fok Ying Tung Education Foundation .
PY - 2013/8/26
Y1 - 2013/8/26
N2 - 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.
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.
KW - Alzheimer's disease
KW - Ferritin light chain
KW - Iron
KW - PEN-2
KW - γ-Secretase
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U2 - 10.1016/j.neulet.2013.05.018
DO - 10.1016/j.neulet.2013.05.018
M3 - Article
C2 - 23685131
AN - SCOPUS:84880137264
SN - 0304-3940
VL - 548
SP - 90
EP - 94
JO - Neuroscience Letters
JF - Neuroscience Letters
ER -