title: Ferritin light chain interacts with PEN-2 and affects γ-secretase activity.
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.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, People's Republic of China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Li
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Liu
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zheng
authors.forename: Guorui
authors.initials: G
authors.lastname: Yao
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.forename: Yun-wu
authors.initials: YW
authors.lastname: Zhang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D001052:Apoferritins / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C469349:PSENEN protein, human; D001052:Apoferritins; D053829:Amyloid Precursor Protein Secretases
keywords: AD; APP; Alzheimer's disease; Aβ; CTF; FTH; FTL; Ferritin light chain; HEK293 cells stably expressing human APP Swedish mutations; HEK293Swe; Iron; NICD; NTF; PEN-2; PS1 or PS2; amino-terminal fragment; carboxyl-terminal fragment; ferritin heavy chain; ferritin light chain; notch intracellular domain; presenilin 1 or 2; β-amyloid; β-amyloid precursor protein; γ-Secretase