Presenilin-Mediated Signaling
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Presenilin-Mediated Signaling
Presenilins are polytopic transmembrane proteins, mutations in which are associated with the occurrence of Early-onset familial Alzheimers disease, a rare form of the disease that results from a single-gene mutation. The physiological functions of Presenilins are unknown, but they may be related to Developmental signaling, Apoptotic signal transduction, or processing of selected proteins, such as the Beta-APP (Beta-Amyloid Precursor protein). Presenilin homologues identified in species that do not have an Alzhemiers disease suggests that they may have functions unrelated to the disease, homologues having been identified in Mouse, Drosophila melanogaster, Caenorhabditis elegans and other members of the eukarya including Plants. In humans, there are two known Presenilins, PS1 (Presenilin-1) and PS2 (Presenilin-2). PS1 and PS2 proteins are composed of 467 and 448 amino acids, respectively, and are 67% identical. Both of them contain eight predicted transmembrane domains and a hydrophilic loop of approximately 120 amino acids between the sixth and seventh transmembrane domains. PS1 and PS2 appear to be ubiquitously expressed throughout the body, with PS1 usually being the more abundant of the two. Within the brain, PSs are expressed in both nerve and glial cells, in NFTs (Neurofibrillary Tangles) and in SPs (Senile Plaques). Within cells, the PSs were initially thought to be predominantly localized to the ER (Endoplasmic Reticulum) and Golgi but, there are more-recent reports of cell-surface expression. A major function of the PSs are their role within the Gamma-Secretase complex, and this complex processes a variety of targets including APP (Amyloid Precursor Protein), Notch, LRP (Lipoprotein Receptor-Related Protein), Cadherin family members, APLP1/2 (Amyloid-Beta-A4 Precursor-Like Protein-1/2), Notch homologs and Notch ligands Delta and Jagged, ErbB4 (v-ErbB2 Avian Erythroblastic Leukemia Viral Oncogene Homolog-4). Other PS interacting proteins include Ctnn-Beta (Catenin-Beta) and MOCA (Modifier Of Cellular Adhesion) (Ref.1 & 2).

APP is the major substrate for PS1 enzymatic activity. Only the N-terminus of PS2 containing the secretory signal sequence, not the cytosolic form, interacts with APP. APP is an integral membrane protein processed by the three proteases Alpha-, Beta-, and Gamma-Secretase, which have been implicated in the cause of AD (Alzheimers Disease). Beta-Secretase or BACE (Beta-site APP-Cleaving Enzyme), a membrane-bound Aspartyl protease, cleaves APP to generate the N-terminus of ABeta (Amyloid-Beta) within the C-terminal APP membrane-bound fragment of 99 amino acids, termed C99 or Beta-CTF. In contrast, Alpha-Secretase cuts within the ABeta region to produce APP-Alphas, an 83-residue COOH-terminal fragment (C83). Another cleavage within the hydrophobic TMD (Transmembrane Domain) generates and releases ABeta from APP. This enigmatic intramembrane cleavage event, also termed RIP (Regulated Intramembrane Proteolysis), has been attributed to Gamma-Secretase. The Gamma-Secretase cleavage occurs at two principle sites to produce the ABeta residues 1-40 (ABeta40) or a longer, more amyloidogenic form containing residues 1-42 (ABeta42). The Gamma-Secretase is a multiprotein complex, which includes Presenilin, PEN2 (Presenilin Enhancer-2 homolog (C. elegans)), APH1 (Anterior Pharynx Defective-1) and Ncstn (Nicastrin). Co-expression of Presenilin, APH1, PEN2 and Nicastrin, but not any three of these four proteins alone, increases Gamma-Secretase activity. Several physiological functions have been attributed to APP, such as neuronal migration, cell survival, trophic properties and axonal transport cargo receptor. Loss of APP and its homolog, APLP2, however, show early postnatal lethality without overt morphological changes in the brain (Ref. 3 & 4).

Presenilin is not only involved in the intramembranous processing of APP but also in the processing of and signaling from the Notch receptor. Proper Notch signaling is critical to a wide variety of cell fate determinations during embryonic development and adulthood. Like APP, Notch is a large, single transmembrane cell surface protein that undergoes proteolytic processing within the secretory pathway. Upon synthesis, the Notch1 receptor undergoes Furin-like cleavage at site S1, forming a heterodimer with the cleaved fragments that is expressed on the plasma membrane. The binding of ligands, such as DSL (Delta/Serrate/Lag-2) family proteins, at the plasma membrane induces endoproteolysis of Notch1 by the ADAM/TACE/Kuzbanian family. This cleavage occurs at S2 within the extracellular juxtamembrane region, and results in shedding of the heterodimerized Notch receptor. The resulting transmembrane fragment, referred to as NEXT (Notch Extracellular Truncation), undergoes constitutive Presenilin-dependent intramembrane proteolysis at S3 and S4, which is referred to as “dual-intramembrane proteolysis”. The S3 cleavage occurs at the interface between the membrane and cytosol, thus determining the N-terminus of NICD (Notch Intracellular Domain). The presence of the S4 cleavage near the middle of the transmembrane domain and Flag-tagged NBeta suggests that a putative Notch1 fragment (NBeta) is produced during the sequential proteolysis of Notch receptors. Gamma-Cleavage, which corresponds to S4 cleavage in Notch1, results in the release of NICD. Once it enters the nucleus, NICD converts CSL DNA-binding proteins (CBF1/RBPJK in vertebrates, suppressor of Hairless in Drosophila and Lag1 in Caenorhabditis elegans) from repressor to a transcriptional activator to allow transcription of target genes. Epsilon-cleavage, corresponding to the S3 cleavage site in Notch1, releases the AICD (BetaAPP Intracellular Domain), which has been suggested to regulate transcription. The obligatory role of Presenilin in Gamma-Secretase cleavage places Presenilin in a crucial position in Notch biology; that is, loss of all Presenilin alleles results in a complete Notch deficiency in all metazoans. The Notch pathway negatively regulates the expression of PS1 and in addition, is itself negatively regulated by APP processing, via the binding of Numb and Numb-like to the C-terminal of APP. In addition to its role in development, Notch signaling is involved in a form of Synaptic plasticity known to be associated with learning and memory processes (Ref.5 & 6).

Besides APP and Notch, many other proteins have been found to be the substrate of Gamma-Secretase. These include Notch ligands Delta and Jagged, ApoER2 lipoprotein receptor, ErbB4 receptor tyrosine kinase, CD44 receptor, LRP, p75(NTR) (p75 Neurotrophin Receptor), Nectin-1Alpha, DCC (Deleted in Colon Cancer), Syndecan3, and E- and N-Cadherins. Many of these molecules (DCC, ErbB4, Delta, p75(NTR)) are known to influence neuronal structure and function, as well as being important for nervous system development. ErbB4 is a receptor for Neuregulins, which are a family of growth factor proteins with EGF (Epidermal Growth Factor)-like motifs that are important in heart, mammary gland and nervous system development. Similarly, DCC is the receptor for Netrins, which are important mediators of axonal growth. p75(NTR) is a member of the tumor necrosis factor receptor superfamily and, working together with TRK receptors, p75NTRs create high-affinity binding sites for the neurotrophins. Notably, p75(NTR) has been reported to be a receptor for ABeta, and this binding has been linked to apoptosis. In addition, by associating with Nogo receptor, this complex acts as a receptor for axonal growth inhibitors such as Nogo, MAG and OMgp. Some Cadherins are Gamma-Secretase substrates, and their biology presents another possibility for affecting neurodegeneration. E-Cadherin is cleaved by Gamma-Secretase activity not within the TMD but at the membrane-cytoplasm interface. Recently, N-Cadherin was also shown to be a Gamma-Secretase substrate whose cleavage is stimulated by membrane depolarization. The released C-terminal fragment (N-Cad/CTF2) repressed CREB (cAMP Response Element-Binding Protein)-dependent activation by accelerating the turnover of CBP (CREB-Binding Protein). Thus, Gamma-Secretase cleavage of a substrate, in a transmitter-dependent manner, influences transcription of genes related to learning and memory in a mechanism distinct from that used by Notch (Ref.7 & 8).

PSs also regulate cell adhesion, apoptosis and several cell-signalling processes such as Calcium signaling. Other PS interacting proteins include Nicastrin, Ctnn-Beta and MOCA (for ‘modifier of cellular adhesion’). Presenilin is also involved in the WNT (Wingless-Type MMTV Integration Site Family Member)/Frizzled signaling through Ctnn-Beta. Ctnn-Beta is a cytoskeletal component that enters the nucleus to act as a transcriptional cofactor. WNT signalling increases the amount of Ctnn-Beta in the cytosol by preventing its ubiquitination and degradation by proteasomes. This allows the direct interaction of Ctnn-Beta with members of the LEF1 (Lymphoid Enhancer-Binding Factor-1)/TCF (Transcription Factor) family of transcription factors, which results in activation of the expression of WNT target genes. The stability of Ctnn-Beta is controlled by phosphorylation, most probably by GSK3Beta (Glycogen Synthase Kinase-3-Beta), which targets Ctnn-Beta to the Ubiquitin/Proteasome. AXIN (Axis Inhibitor), which associates directly with Ctnn-Beta, GSK3Beta and the APC (Adenomatous Poliposis Coli) protein, is likely to have an indispensable role in the phosphorylation of Ctnn-Beta by GSK3Beta as a scaffold protein. Presenilin stimulates Ctnn-Beta turnover, reducing its transcriptional activation. In addition to its role in WNT signaling, Ctnn-Beta is a component of the Cadherins-based adherens junction complexes formed at cell-cell adhesion sites. Ctnn-Beta binds the cytoplasmic domain of E-Cadherin distal to the membrane at residues 833-862 and acts as a structural protein by linking cell surface Cadherins to the Actin cytoskeleton. By sequestering Ctnn-Beta at the membrane, Cadherins affect the signaling properties of cytosolic Ctnn-Beta, which may act as a communicator between WNT signaling and cell-cell adhesion. PS1 binds E-Cadherin at amino acids 760-771 close to the membrane/cytoplasm interface (juxtamembrane region). In addition, PS1 forms complexes with the Cadherin/Catenin based adherens junction at the plasma membrane where it functions to stabilize the Cadherin/Ctnn-Beta association and to promote cell-cell adhesion. Under apoptotic or Ca2+-influx conditions, however, PS1 promotes cleavage of the cytoplasmic domain of Cadherins and the release of the Cadherin-associated Ctnn-Beta to the cytosol (Ref.9 & 10).

Presenilins modulate Capacitative Calcium entry, a process that is closely connected to Calcium release from ER (Endoplasmic Reticulum) pools, and that a number of PS1 and PS2 mutations affect Calcium homeostasis. Although Presenilins do not contain any known Calcium-binding motifs, both PS1 and PS2 have been shown to interact with a number of Calcium-related proteins, such as CS (Calsenilin), Sorcin and Calmyrin. This regulation of intracellular Calcium homeostasis by Presenilins also affects Glutamate uptake and Glutamate-evoked Calcium responses in neurons as well as Glutamate-evoked Calcium responses in neurons. Consequently, it has been proposed that destabilization of Calcium signaling has a role in neuronal cell death in AD. Calsenilin/DREAM (DRE-Antagonist Modulator)/KChIP3 is a multifunctional Calcium binding protein, which serves as a Calcium-regulated transcription repressor and binds to A-type voltage-gated potassium channels. Calsenilin is also involved in apoptosis and ABeta production. The effect on intracellular Ca2+ might be mediated by IP3 (Inositol Trisphosphate). Another Ca2+-binding protein, Socrin, also binds to PS1, and modulates intracellular Ca2+ levels through both RyRs (Ryanodine Receptors) and Voltage-gated Ca2+ channels. In addition, other proteins that interact with PS, such as Bcl2 (B-Cell CLL/Lymphoma-2), BclXL (Bcl2 Related Protein Long Isoform), Cadherin and Ctnn-Beta are involved in Ca2+-dependent signalling pathways (Ref.11 & 12).

MOCA/PBP (PS-Binding Protein) also interacts with PS1 and PS2. The region of PS that is responsible for this interaction is localised to a conserved region of PS1 and PS2 (amino acids 375-396 of PS1), within the junctional region between the large loop and TM domain 7 of PS. This region is near the Ctnn-Beta -binding site. MOCA is composed of 2027 amino acids with a predicted molecular mass of 233 kDa, and contains a SH3 (Src-Homology-3) domain at the N-terminus and several Crk-binding motifs near the C-terminus. MOCA belongs to the DOCK family and has 40% homology with DOCK180, a Crk-binding protein that is involved in the regulation of cell movement and morphology. The primary cellular location of MOCA is the cytoplasm; however, overexpression of PS1 relocalizes MOCA to the membrane. Unlike most other PS-binding proteins, MOCA is expressed only in the brain and is highly localised to the cerebral cortex and hippocampus, which are areas prone to cell death in AD. MOCA is also involved in the regulation of cell adhesion (Ref. 2 & 13).

An understanding of the above pathways in CNS nerve cells is a prerequisite to designing therapeutics based upon both the regulation of ABeta production and the mechanisms that mediate its toxicity. Since there is a wide-spread loss of nerve cells and the information they store in AD, it is clear that therapeutics based upon nerve cell replacement will not provide a viable possibility in the foreseeable future, for the information in the cells and their connections will not be replaced and the loss of nerve cells will continue. The complementary approaches of studying the pathology, genetics and biochemistry of AD in humans together with analysis of relevant proteins and pathways in simpler animal systems has led to the best understanding of the normal biological roles of the proteins directly linked to AD through their ability to interact with PS. With the continued contribution of such studies, it should be possible to understand the details of the pathways that lead to nerve cell death in this devastating disease and to design therapeutics based upon this information (Ref.1 & 14).