Identification of the role of presenilins beyond Alzheimer’s disease

Abstract

Mutations in the genes encoding presenilin 1 (PS1) and presenilin 2 (PS2) account for the majority of the cases of familial early-onset Alzheimer’s disease (FAD). Presenilins (PSs) facilitate the intramembraneous cleavage of amyloid precursor protein (APP), coined γ-secretase cleavage, which generates β-amyloid peptides (Aβ). Considerable evidence suggests that FAD-linked PS variants exert their pathogenic influence by selectively elevating the levels of highly fibrillogenic Aβ42 peptides. In addition, numerous other functions have been ascribed to PSs based on subcellular localization, protein interactions, loss of function studies, and intramembraneous γ-secretase cleavage of growing number of substrates. This review summarizes the diverse physiological functions that are regulated by PSs beyond APP metabolism.

Introduction

Since the first description of a genetic link between PS and AD, these homologous polytopic membrane proteins have become the focus of several research groups interested in the molecular mechanisms of Alzheimer’s disease (AD). PS1 functions as a multiprotein complex comprised of at least three other transmembrane proteins namely nicastrin, Aph-1 and Pen-2. Biogenesis of these four proteins and their assembly into high molecular weight complex are highly regulated processes that depend on the availability of each of the component polypeptides in stoichiometric concentrations [1], [2], [3]. PS1 is synthesized as a 42- to 43-kDa polypeptide that undergoes endoproteolytic processing within the cytoplasmic loop connecting putative transmembrane segments 6 and 7 to generate stable 27- to 28-kDa N-terminal (NTF) and 16- to 17-kDa C-terminal (CTF) proteolytic derivatives [4]. In transfected cells only a fraction of overexpressed PS1 is converted to stable NTF and CTF, whereas the majority of nascent PS1 polypeptide is rapidly degraded, indicating that the accumulation of PS1 NTF and CTF is tightly regulated and saturable [4], [5]. Thus, endoproteolysis of PSs is a highly conserved process and, arguably, a processing event that regulates the accumulation of fragments, and at least some biological functions of PS. Direct evidence that the NTF/CTF assembly is part of the active γ-secretase enzyme complex came from studies that developed transition state analogue inhibitors of aspartyl proteases. Two such reagents specifically bound to PS1 NTF and CTF, and not to PS1 holoprotein, supporting the notion that endoproteolytic derivatives are the biologically active forms of PS1 [6], [7]. Recent evidence shows that PS1 endoproteolysis and accumulation of fragments are regulated by the availability of nicastrin, Aph-1 and Pen-2 [1], [2], [3]. Human PS1 expressed in yeast along with these three cofactors undergoes proteolytic processing to generate stable PS1 NTF and CTF [8]. Furthermore, coexpression of all four proteins is sufficient to overcome the limitation in generating excess PS-derived NTF and CTF in transfected cells [1], [2], [3].

Genetic, biochemical, and pharmacological evidence points to an active role for nicastrin, Aph-1 and Pen-2 in PS1-mediated intramembraneous γ-secretase processing of select type I membrane proteins. All three proteins were first identified by genetic screens performed in Caenorhabditis elegans and subsequently shown to be stoichiometric components of high molecular weight complexes that exhibit γ-secretase activity. Interestingly, each of these proteins appears to be codependent for biogenesis, maturation and stability. For example, the highly glycosylated type I membrane protein nicastrin does not mature and exit the ER in cells lacking PS1 expression [9]. Conversely, PS1 fails to undergo endoproteolysis to generate stable NTF and CTF in nicastrin^−/− cells [10]. Thus, it is clear now that γ-secretase activity depends on stoichiometric expression of each of these components and their proper assembly and trafficking to appropriate subcellular location. Details on the assembly of the γ-secretase complex are only beginning to emerge, and available evidence supports the formation of an early intermediate sub-complex of Aph-1 and nicastrin [11]. Unfortunately, several pharmacological inhibitors selected based on their ability to inhibit Aβ production do not seem to markedly affect PS1 complex formation and localization [12], [13], thus presenting researchers with the challenge of developing additional unique reagents to explore the details of the PS1/γ-secretase complex assembly process.