The very many faces of presenilins and the γ-secretase complex

Abstract

Presenilin is a central, catalytic component of the γ-secretase complex which conducts intramembrane cleavage of various protein substrates. Although identified and mainly studied through its role in the development of amyloid plaques in Alzheimer disease, γ-secretase has many other important functions. The complex seems to be evolutionary conserved throughout the Metazoa, but recent findings in plants and Dictyostelium discoideum as well as in archeons suggest that its evolution and functions might be much more diversified than previously expected. In this review, a selective survey of the multitude of functions of presenilins and the γ-secretase complex is presented. Following a brief overview of γ-secretase structure, assembly and maturation, three functional aspects are analyzed: (1) the role of γ-secretase in autophagy and phagocytosis; (2) involvement of the complex in signaling related to endocytosis; and (3) control of calcium fluxes by presenilins.

Corrupted ER‐mitochondrial calcium homeostasis promotes the collapse of proteostasis

“…While altered presenilin function has been known to have a role in AD for over 20 years, the functional consequences of presenilin mutations are not understood (Selkoe & Hardy, ). Presenilins are an ancient conserved protein family that are found on endomembranes in plants, amoeba, invertebrates, and mammals, including humans (Levitan & Greenwald, ;Smolarkiewicz et al, ). However, their function on endomembranes has not been explored in great detail.…”

“…However, despite the identification of presenilin's association with AD over 20 years ago, their role in AD is not understood (Kelleher & Shen, ;Selkoe & Hardy, ). Presenilins are widely expressed predominantly endoplasmic reticulum (ER) membrane proteins that form the proteolytic subunit of the gamma secretase, which is an integral membrane protein complex that cleaves single‐pass transmembrane proteins (De Strooper, Iwatsubo, & Wolfe, ;Smolarkiewicz, Skrzypczak, & Wojtaszek, ). Previously using Caenorhabditis elegans as a model system to understand presenilin function, we found that mutations in the C. elegans presenilin gene ( sel‐12 ) cause elevated ER to mitochondria calcium signaling, which leads to an increase in mitochondrial calcium content that results in increased mitochondrial oxidative phosphorylation and electron leak accelerating oxidative stress (Sarasija et al, ).…”

Aluminum toxicity related to SOD and expression of presenilin and CREB in Bombyx mori

“…Al exposure has been proposed as an environmental factor associated with pathological changes related to neurotoxicity and implicated in the etiology of the cognitive dysfunction associated with neurodegenerative diseases such as AD (Maya et al., ; Shaw & Tomljenovic, ). Presenilin affects the generation and aggregation of Aβ and plays a critical role in the development of AD (Smolarkiewicz et al., ). In a rat model of Al neurotoxicity established using d ‐galactose and AlCl 3 , PS1 mRNA expression was approximately twofold higher relative to the control, with a similar trend observed in terms of protein expression levels (Wang et al., ).…”

“…SOD inactivates free radicals in living tissues and reduced SOD levels have been associated with accelerated aging, reduced lifespan duration, and vision loss (Bondy, ; Savory, Herman, & Ghribi, ). Genes coding for presenilins harbor approximately 90% of the mutations, which is potentially responsible for early‐onset familial AD, a neurodegenerative disorder characterized by progressive loss of memory and cognitive ability (Smolarkiewicz, Skrzypczak, & Wojtaszek, ; Tanzi, ). In Al‐treated animals, it has been demonstrated that Al enter the brain and disrupt learning and memory functions by enhancing the production and aggregation of amyloid‐β (Aβ) in vitro and in vivo, with a marked increase in the expression of enzymes participating in Aβ metabolism such as presenilin (Kawahara, Kato, & Kuroda, ; Matsuzaki et al., ; Walton & Wang, ; Wang et al., ).…”

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

“…Presenilins as well as the other components of the γ-secretase complex are an ancient family that are conserved throughout evolution and have been identified in such diverse organisms as plants, amoeba and multicellular animals (Smolarkiewicz et al, 2013). Intriguingly, while APP and Notch are well-studied substrates of the γ-secretase, both Notch and APP are not conserved in plants or amoeba.…”