PSEN1 Membrane Protein Introduction

Introduction of PSEN1

Presenilin-1 (PS-1) is a presenilin protein encoded by the PSEN1 gene in humans. PSEN1 is one of the four core proteins in the gamma secretase complex, which is thought to play an important role in the production of amyloid β (Aβ) from amyloid precursor protein (APP). PSEN1 has nine transmembrane domain topologies with an extracellular C-terminus and a cytoplasmic N-terminus, which are produced in humans by proteolytic processing. In addition, PSEN1 is present in cells as a heterodimer of the C-terminal and N-terminal fragments. When PSEN1 is overexpressed, the full-length protein accumulates in an inactive form.

Function of PSEN1 membrane protein

PSEN1 acts as a catalytic subunit of the gamma-secretase complex, an endoprotease complex, which regulates APP processing through its action on gamma secretase, an enzyme that cleaves APP. PSEN1 is also thought to be involved in the cleavage of Notch receptors such that they directly modulate gamma secretase activity or their own proteases. PSEN1 plays a role in the regulation of the Notch and Wnt signaling cascades and downstream processes by its role in the processing of key regulatory proteins and by regulation of cytosolic CTNNB1 levels. PSEN1 is shown to stimulate cell-cell adhesion via interaction with CDH1, which stabilizes the complex between CDH1 and its interaction partner CTNNB1 (β-catenin), CTNND1 and JUP (γ-catenin). CDH1 is cleaved under conditions of apoptosis or calcium influx. Therefore, this promotes the breakdown of the complex between CDH1 and CTNND1, JUP and CTNNB1, finally negatively regulating Wnt signaling. In addition, PSEN1 is required for normal embryonic brain and bone development as well as normal angiogenesis.

Fig.1 Schematic representation of PS1 sequence and topology. (Dillen, 2006)

Application of PSEN1 membrane protein in Literature

1. Coupland K.G., et al. Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer's disease. Current Alzheimer Research. 2015, 12(8):745-751. PubMed ID: 26159201
   
   

   The authors found that the brain region specificity of the MAPK promoter methylation in PSEN1 AD patients is decreased, indicating a novel effect of PSEN1 on MAPT methylation and suggesting a specific role for PSEN1 mutation.

2. Deng H., et al. The miR-193a-3p regulated PSEN1 gene suppresses the multi-chemoresistance of bladder cancer. Biochimica Et Biophysica Acta. 2015, 1852(3):520-8. PubMed ID: 25542424
   
   

   This article suggests that PSEN1 may have a positive effect on the multi-chemotherapy resistance of bladder cancer by activating the pathway of DNA damage response, which acts as a key participant in the microRNA-193a-3p/PSEN1 axis and may be a therapeutic target for effective chemotherapy of bladder cancer.

3. Testi S., et al. A novel PSEN1 mutation in a patient with sporadic early-onset Alzheimer's disease and prominent cerebellar ataxia. Journal of Alzheimers Disease Jad. 2014, 41(3):709. PubMed ID: 24718101
   
   

   The article reports a novel PSEN1 mutation that causes sporadic early-onset dementia with prominent cerebellar symptoms, similar to the spinal cerebellar syndrome, broadening the unusual phenotype associated with PSEN1 mutations.

4. Newman M., et al. Differential, dominant activation and inhibition of Notch signaling and APP cleavage by truncations of PSEN1 in human disease. Human Molecular Genetics. 2014, 23(3):602. PubMed ID: 24101600
   
   

   The authors' work shows that various truncations of human PSEN1 protein have distinctly different effects on Notch signaling and cleavage of zebrafish App, suggesting new hypotheses for the pathogenesis of Alzheimer's disease.

5. Azimi M., et al. Presenilin gene function and Notch signaling feedback regulation in the developing mouse lens. Differentiation. 2018, 102:40-52. PubMed ID: 30059908
   
   

   The article reveals a novel genetic interaction between Psen1 and Jagged1, and concludes that regulation of Notch2 protein levels is particularly important during normal signaling and post-translational regulation.

PSEN1 Preparation Options

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Reference

1. Dillen K and Annaert W. (2006). A Two Decade Contribution of Molecular Cell Biology to the Centennial of Alzheimer's Disease: Are We Progressing Toward Therapy. International Review of Cytology. 254:215-300.

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