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Role of the presenilins
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A major function of the PSs are their role within the γ-secretase complex, and in addition to APP, this complex processes a variety of other targets, for example Notch, LRP, Cadherin family members, APLP1/2, Notch homologs and Notch ligands delta and jagged, ErbB4 (reviewed by Koo and Kopan 2004 These additional targets are localised to detergent soluble membrane domains, indicating that these processing events are distinct to APP processing (Vetrivel et al 2005 The PSs also mediate a variety of other interactions. The following description of the functions of the PSs is by no means exhaustive, but provides an overview of perhaps the most relevant roles of this protein.

Notch processing

The Notch family of proteins encode a family of large type-I transmembrane receptors that determine cell fate and regulate pattern formation. Processing of Notch is activated at the cell surface by binding of extracellular ligands that belong to the DSL (Delta, Serrate and Lag-2) family. This facilitates the shedding of the Notch ectodomain by the α-secretases, TACE and ADAM10, and the resulting membrane bound fragment is targeted at the S3-cleavage site by γ-secretase. This leads to the release of the Notch intracellular domain (NICD), which is analogous to AICD. The NICD contains a nuclear localisation signal and it translocates to the nucleus where it interacts with CSL proteins (CBF, Su H, and Lag-1) to modify transcription of specific genes.

The phenotype of Notch knock-out mice is perinatally lethal and almost identical to PS double knock-out mice (Donoviel et al 1999 Herreman et al 1999 confirming the involvement of PSs in Notch processing. Notch and APP compete with each other for processing (Lleo et al 2003 however, they do not compete for binding, confirming the presence of a PS dimer with distinct binding and active site (Schroeter et al 2003 Furthermore, specific regions of PS are critical for substrate-specific γ-secretase processing, as mutations within TM5 of PS1 and PS2 differentially affect the production of C99 and NICD indicating that this region is important for γ-cleavage of APP but not Notch (Walker et al 2005 The Notch pathway negatively regulates the expression of PS1 (Lleo et al 2003 and in addition, is itself negatively regulated by APP processing, via the binding of Numb and Numb-like to the C-terminal of APP (Roncarati et al 2002 In addition to its role in development, Notch signalling is involved in a form of synaptic plasticity known to be associated with learning and memory processes (Wang et al 2004

N-Cadherin Processing

CREB-dependent gene expression is critical for the function and plasticity of the nervous system, including long term memory and learning. Neuronal (N’)-cadherin is a transmembrane protein with important neuronal and synaptic functions. PS1 mediates transport of N-cadherin to the plasma membrane (Uemura et al 2003 and may regulate the binding of pre- and post-synaptic membranes (Georgakopoulos et al 1999 Processing of N-cadherin by γ-secretase is also analogous to that of APP, and generates a C-terminal domain that may promote degradation of the transcriptional co-activator, CREB-binding protein (CBP). This leads to the suppression of CREB-mediated gene transcription (Marambaud et al 2003 However, PS deficient mice have reduced levels of CREB-induced genes, indicating that although the precise regulatory mechanism of PS is unclear, PS does affect CREB-dependent transcription.

Wnt signalling

The Wnt family are a group of extracellular glycoproteins that regulate homeostasis and development by binding to membrane-bound members of the Frizzled (Fzd) family and the LRP5/6 co-receptors. Canonical Wnt signalling leads to the stabilisation of cytosolic pools of -catenin and induction of gene expression (reviewed by De Ferrari and Inestrosa 2000 Moon et al 2004 Nelson and Nusse 2004 In the presence of a Wnt ligand, an intracellular signal is transduced via activation of the Dishevelled (Dvl) protein. Membrane recruitment of Dvl recruits Axin, APC and GSK-3β to the plasma membrane where Axin binds to the cytoplasmic tail of LRP5/6. This leads to the degradation of axin, which decreases degradation of β-catenin. Furthermore, activation of Dvl leads to the inhibition of GSK-3, which further reduces the degradation of β-catenin. Different pools of -catenin exist, and it is primarily located at the cell membrane in complex with E-cadherin: this pool is not affected by Wnt signalling. Wnt signalling increases cytosolic β-catenin and it translocates to the nucleus where it interacts with components of the high-mobility group of transcription factors TcF/LEF and activates transcription of genes such as Cyclin D1. In the absence of a Wnt ligand, GSK-3 remains active and phosphorylates -catenin targeting it for degradation via the proteasome degradation pathway. Wnt signalling can be auto-regulated via negative feedback mechanisms that induce expression of Dkk1, a negative regulator of Wnt signalling (Gonzalez-Sancho et al 2005 Non-canonical Wnt signalling pathways lead to the activation of kinases JNK and PKC, or small G proteins such as Rho and Rac.

Wnt signalling interacts with and regulates other signalling pathways. One such pathway is PI3K signalling, which is stimulated via induction of IGFII (Sinha et al 2005 Furthermore, PS1 interacts with components of the Wnt signalling cascade. It binds to β-catenin and negatively regulates both its stability and transcriptional activity (Killick et al 2001 These effects on transcription are independent of GSK-3β phosphorylation (Killick et al 2001 and may involve binding of PS to E-cadherin (Baki et al 2001 which stimulates binding to -catenin and inhibits transcription (Gottardi et al 2001 Both PS and β-catenin can be phosphorylated by p35/Cdk5 (Kwon et al 2000 Lau et al 2002 and this may regulate their binding (Kesavapany et al 2001 In addition to β-catenin, PS1 binds independently to GSK-3 and tau, via the microtubule repeat region, and is possibly a docking-regulator (reviewed by De Ferrari and Inestrosa 2000

PS1 mutations have reduced ability to bind to β-catenin, thus leading to increased β-catenin (Killick et al 2001 In addition, mutations in the tau binding region of PS1 increase binding to GSK-3β and increase its tau-directed kinase activity (Takashima et al 1998a In contrast to PS mutations, cells expressing APP mutations have decreased nuclear -catenin (Kim et al 2003a and experiments indicate that GSK-3α (Phiel et al 2003 and GSK3 (Su et al 2004 play a role in APP processing. GSK3β activity is further regulated by PKC signalling, and deficits in this signalling pathway are observed in AD brains (Chen et al 2000 Normal activation of PKC is mediated by Dvl, which has been shown to increase sAPPα via JNK and PKC signalling (Mudher et al 2001 Regulation of PKC may also occur through Notch signalling: Dvl interacts with the C-terminus of Notch, and Wnt signalling blocks Notch signalling (Axelrod et al 1996 indicating crosstalk between these pathways at the level of Dvl and possibly also PSs. Furthermore, Wnt signalling is potentially linked to APP function. Increased levels of A leads to increased p53 and induction of Dkk1 expression, which results in inhibition of Wnt signalling and decreased inhibition of GSK-3 (Caricasole et al 2004

Wnt signalling may function in regulation of cognitive processes. Destabilisation of endogenous -catenin is observed in rats injected with preformed A fibrils, and there is also evidence of neurodegeneration and behavioural impairments (De Ferrari et al 2003

Summary

PSs clearly function in a variety of signalling pathways. FAD PS mutations could influence cognition through these pathways, as well as through APP metabolism, and in addition provide a link between plaque and tangle pathology.

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