PSEN1

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Presenilin 1
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PSEN1 ; AD3; FAD; PS-1; PS1; S182
External IDs OMIM104311 MGI1202717 HomoloGene7186 ChEMBL: 2473 GeneCards: PSEN1 Gene
EC number 3.4.23.-
RNA expression pattern
PBB GE PSEN1 203460 s at tn.png
PBB GE PSEN1 207782 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5663 19164
Ensembl ENSG00000080815 ENSMUSG00000019969
UniProt P49768 P49769
RefSeq (mRNA) NM_000021 NM_008943
RefSeq (protein) NP_000012 NP_032969
Location (UCSC) Chr 14:
73.6 – 73.69 Mb
Chr 12:
83.69 – 83.74 Mb
PubMed search [1] [2]

Presenilin-1 (PS-1) is a protein that in humans is encoded by the PSEN1 gene.[1] Presenilin 1 is one of the four core proteins in presenilin complex, which mediate the regulated proteolytic events of several proteins in the cell, including gamma secretase.[2] Gamma-secretase is considered to play a very important role in generation of beta amyloid, accumulation of which is related to the onset of Alzheimer’s Disease, from the beta-amyloid precursor protein.[3]

Structure[edit]

Presenilin possesses a 9 transmembrane topology, with an extracellular C-terminus and a cytosolic N-terminus.[4][5] Presenilin is subject to undergo endo-proteolytic processing to produce ~27-28 kDa N-terminal and ~16-17 kDa C-terminal fragments in humans.[6] Furthermore, presenilin exists in the cell mainly as a heterodimer of the C-terminal and N-terminus fragments.[6] When presenilin 1 is over expressed, the full length protein accumulates in an inactive form.[7] Based on evidence that a gamma-secretase inhibitor binds to the fragments,[8] the cleaved presenilin complex is considered to be the active form.[9]

Function[edit]

Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma secretase activity or themselves are protease enzymes. Multiple alternatively spliced transcript variants have been identified for this gene, the full-length natures of only some have been determined.[10]

Role in beta-amyloid production[edit]

Transgenic mice that over-expressed mutant presenilin-1 show an increase of beta-amyloid-42(43) in the brain, which suggest presenilin-1 plays an important role in beta-amyloid regulation and can be highly related to Alzheimer’s disease.[11] Further study conducted in neuronal cultures derived from presenilin-1 deficient mouse embryos. They showed that cleavage by alpha- and beta- secretase was still normal without the presence of presenilin-1. Meanwhile, the cleavage by gamma-cleavage of the transmembrane domain of APP was abolished. A 5-fold drop of amyloid peptide was observed, suggesting that deficiency of presenilin-1 can down regulate amyloid and inhibition of presenilin-1 can be a potential method for anti-amyloidogenic therapy in Alzheimer’s disease.[12] Extensive study on the role of presenilin-1 in amyloid production has been conducted to improve our understanding of Alzheimer’s disease.[13][14]

Role in Notch signaling pathway[edit]

In Notch signaling, critical proteolytic reactions takes place during maturation and activation of Notch membrane receptor.[15] Notch1 is cleaved extracellularlly at site1 (S1) and two polypeptides are produce to form a heterodimer receptor on the cell surface.[16] After the formation of receptor, Notch1 is further cleaved in site 3(S3)[17] and release Notch1 intracellular domain (NICD) form the membrane.[18]

Presenilin 1 has been shown to play an important role in proteolytic process. In the prenilin 1 null mutant drosophila, Notch signaling is abolished and it displays a notch-like lethal phenotype.[19] Moreover, in mammalian cells, deficiency of PSEN1 also causes the defect in the proteolytic release of NICD from a truncated Notch construct. The same step can be also blocked by several gamma-secretase inhibitors, shown in the same study.[20] These evidences collectively suggest a critical role of presenilin 1 in the Notch signaling pathway.

Role in Wnt signaling pathway[edit]

Wnt signaling pathway has been shown to be involved in several critical steps in embryogenensis and development. Presenilin 1 has been shown to form a complex with beta-catenin, an important component in Wnt signaling, and stabilized beta-catenin.[21] Mutant of presenilin-1 that reduces the ability to stable beta-catenin complex will lead to hyperactive degradation of beta-catenin in the brains of transgenic mice.[21]

Considered as a negative regulator in wnt signaling pathway, presenilin-1 was also found to be played a role in beta-catenin phosphorylation.[22] Beta-catenin is coupled by presenilin-1 and under a sequential phosphorylation by two kinase activities.[22] The study also further illustrates the deficiency of presenilin 1 will disconnect the sequential phosphorylation and thus disrupt the normal wnt signaling pathway.[22]

Role in cancer[edit]

In addition to its role in Alzheimer’s disease, presenilin-1 also found to be important in cancer. A study of broad range gene expression was conducted on human malignant melanoma. Researchers classified the malignant melanoma cell lines into two types. The study showed that presenilin-1 is down regulated in cell type while it is overexpressed in the other cell type.[23] Another study on multidrug resistance (MDR) cell line also reveals a role of presenilin-1 in cancer development. Because of the development to the resistance to chemical, MDR cells become a critical factor on the success of cancer chemotherapy.[24] In the study, researcher tried to explore the molecular mechanism by looking into the expression of Notch1 intracellular (N1IC) domain and presenilin 1. They found that there is higher level expression of both protein and a multidrug resistance-associated protein 1 (ABCC1) was also found to be regulated by N1IC, which suggest a mechanism of ABCC1 regulated by presenilin 1 and notch signaling.[25]

Interactions[edit]

PSEN1 has been shown to interact with:

References[edit]

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Further reading[edit]

External links[edit]