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.

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…APP has a 5′ untranslated region ironresponsive element [140]; in conditions of high iron (e.g., AD) restricted translation of APP by iron-responsive proteins is disinhibited, leading to increased translation of the transcript. High iron conditions also leads to increased processing of APP [141], which leads to accelerated degeneration in a mouse model of AD [142]. Iron is particularly enriched in plaques [99], and iron causes the aggregation of Aβ in vitro [143,144].…”

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…A possible involvement of ferritin in pathomechanisms of neurodegeneration may be also linked to novel non-iron-related functions (see below). Interesting examples are the binding between FtH and CXCR4 and FtL and Pen2 (Li et al 2013). In the first case the interaction results in a negative modulation of the CXCL12/CXCR4 pathway, which is known to regulate neuronal migration, differentiation and survival.…”

“…Interestingly, the reduction in FtH content was also associated with a less robust viral infection, thus indicating that FtH may be a host factor required for HCV infection (Mancone et al 2012). On the basis of the possible role of iron in the development of neurodegenerative processes, it is of particular interest a recent report showing that FtL can interact with Pen-2, a subunit of the multiprotein complex associated with the -secretase activity, involved in the processing of the amyloid precursor protein (Li et al 2013).The interaction has been found by the yeast two hybrid system and co-immunoprecipitation of the two proteins in cells overexpressing them. FtL overexpression or its induction by iron resulted in Pen-2 stabilization and increased betaamyloid production due to stimulation of the -secretase activity.…”

Iron increases APP translation and amyloid-beta production in the retina

“…Prior studies suggest that iron may affect secretase enzymes involved in APP processing (Bodovitz et al, 1995; Kim and Yoo, 2013; Li et al, 2013; Xiong et al, 2007). To determine whether this effect contributes to the observed iron-induced generation of APP cleavage products, we measured protein levels and cleavage activities of α- and β-secretases in ARPE-19 cells treated with iron (FAC) or the iron chelator, deferiprone (DFP).…”