Identification of the role of presenilins beyond Alzheimer’s disease
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.
Section snippets
Intramembraneous cleavage of type I membrane proteins
In the past few years there has been accumulating interest in understanding regulated cleavage of type I membrane proteins within their transmembrane domains (TMs). In keeping with the nomenclature of previously described α- and β-secretase cleavage of APP within the extracellular domain, the intramembraneous cleavage of APP was termed the “γ-secretase” cleavage. In the case of APP, γ-secretase cleavage at two major sites within the TM was identified, which result in the generation of Aβ
Presenilin-interacting proteins
As described above, PS-derived NTF and CTF are components of high molecular weight complexes. Over the past few years several investigators employed yeast two-hybrid assays and candidate approaches to identify a growing number of proteins that interact with various domains of PS1 or PS2 [31]. The list of PS-interacting proteins includes: members of a family of armadillo-related proteins, including β-catenin (see the following); cell-surface transmembrane protein E-cadherin; filamin, an
Functional role for PS1 in regulating β-catenin
The most interesting information uncovered by the two-hybrid binding studies employing PS1 is the association with members of a family of armadillo-related proteins. First described by Zhou et al. [34], PS has been shown to interact with β-catenin, γ-catenin, δ-catenin, p0001, and neural-specific plakophilin. Since β-catenin is a multifunctional protein involved in Wnt signal transduction, cell adhesion and tumor progression, the functional significance of PS β-catenin interaction has been
PS1 and neurogenesis
Notch activity is essential for a wide variety of cell fate decisions during development [45]. In the adult, Notch activity also plays a fundamental role in the adult in regulating neurite outgrowth, maintenance of the hematopoietic system, etc. A recent review by Selkoe and Kopan [24] has detailed description of how PS1 function impacts on Notch activity during development. Notch receptors and ligands continue to be expressed in post-mitotic cortical neurons, and cytoplasmic domain of
PS1 function in cell adhesion and synapse formation
PS1 is ubiquitously expressed in peripheral tissue and in the nervous system. Several studies have investigated the subcellular localization PS1 in neurons using biochemical methods, immunostaining, and immunoelectron microscopy [54], [55], [56], [57]. In addition to the expected localization in intracellular membranes (such as the ER and Golgi) based on cell culture studies, PS1-drived fragments in neurons were also found in small synaptic vesicles, synaptic plasma membranes, synaptic adhesion
PS and cellular substrates of memory
The development of transgenic mouse models based on genes that are mutated in individuals with familial early-onset Alzheimer’s disease has greatly advanced our understanding of the pathogenesis of this debilitating disorder [65]. Despite the success of these efforts, little attention has been directed towards the understanding of basic physiology of memory storage in these animal models [66]. Few studies have investigated synaptic transmission and LTP, which contribute to several forms of
Regulation of Ca2+ homeostasis and apoptosis
Nearly a decade ago it was observed that inositol trisphosphate (IP3)-mediated intracellular Ca2+ release was enhanced in fibroblasts from patients with AD [74]. Neither voltage-dependent Ca2+ influx, nor release of endoplasmic reticulum Ca2+ stores by exposure to thapsigargin was different for AD and control fibroblasts. Although this study included fibroblasts derived from familial and nonfamilial cases of AD, subsequent studies demonstrated significant potentiation of IP3-evoked Ca2+ release
Conclusions
Inhibition of Aβ production by interfering with PS1/γ-secretase activity is considered as one of the potential therapeutic strategy for the treatment of Alzheimer’s disease, and several inhibitors that target to PS-derived fragments and lower Aβ production have been developed. However, the accumulating evidence that APP, Notch and other unidentified transmembrane proteins share similar intramembraneous proteolytic processing pathways compels us to reconsider the merit of this strategy. Based on
Acknowledgements
The authors are supported by grants from the National Institutes of Health, the Alzheimer’s Association and American Health Assistance Foundation.
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Trafficking in neurons: Searching for new targets for Alzheimer's disease future therapies
2013, European Journal of PharmacologyCitation Excerpt :Moreover, the substrates APP and Notch were shown to compete for proteolysis but not for binding to PS under saturating condition (Schroeter et al., 2003). Several studies demonstrate that certain PS domains have different functions independently of their role in the γ-secretase complex (Thinakaran and Parent, 2004). For example, the hydrophilic loop of PS1 represents the domain of interaction with β-catenin, and this association functions as a negative regulator of the Wnt/β-catenin signaling pathway (Kang et al., 2002; Soriano et al., 2001).
Mouse models of Alzheimer's disease
2012, Brain Research BulletinIntraperitoneal injection of JNK-specific inhibitor SP600125 inhibits the expression of presenilin-1 and Notch signaling in mouse brain without induction of apoptosis
2012, Brain ResearchCitation Excerpt :PS1, PS2, and γ-secretase also cleave a variety of other type 1 transmembrane proteins which all release intracellular fragments (ICD) with the ability to interact with transcription co-activators (Koo and Kopan, 2004; Kopan and Goate, 2000). Hence PS1 and PS2 may affect the expression of many genes through intramembrane proteolysis (Thinakaran and Parent, 2004). Therefore, we have studied the transcriptional control of the PS1 gene.
Aberrant regulation of alternative pre-mRNA splicing in schizophrenia
2010, Neurochemistry InternationalCitation Excerpt :The presenilins (PSs) have been identified as causative genes for familial Alzheimer's disease (AD); they are required for the regulation of the intramembrane proteolysis of amyloid precursor protein, another causative gene for familial AD. In addition, PSs have an important role in Notch, ERBB4, E-cadherin and WNT signaling and are also associated with schizophrenia (Ide et al., 2004; Law et al., 2007; Lee et al., 2002; Marambaud et al., 2002; Roperch et al., 1998; Sardi et al., 2006; Soriano et al., 2001; Takashima et al., 1998; Thinakaran and Parent, 2004; Wei and Hemmings, 2000). Furthermore, the PS2 gene has been genetically associated with SZ (Zhang et al., 2009).
Does the presenilin 2 gene predispose to schizophrenia?
2009, Schizophrenia Research