Biology of presenilins as causative molecules for Alzheimer disease

@article{Nishimura1999BiologyOP,
  title={Biology of presenilins as causative molecules for Alzheimer disease},
  author={Masaki Nishimura and G. Yu and Peter H St George-Hyslop},
  journal={Clinical Genetics},
  year={1999},
  volume={55}
}
Many missense mutations in the presenilins are associated with autosomal dominant forms of familial Alzheimer disease (AD). Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high‐molecular‐weight complexes under physiological conditions. The presenilins have been suggested to be functionally involved in developmental morphogenesis, apoptosis signal pathways, and processing of selected proteins including β‐amyloid precursor protein… 
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  • Q. Guo, Jun Xie
  • Biology, Chemistry
    Journal of Biological Chemistry
  • 2004
TLDR
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References

SHOWING 1-10 OF 61 REFERENCES
Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin,a component of the presenilin protein complex
TLDR
It is reported here that presenilin mutations associated with familial Alzheimer disease (but not the non–pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of β-catenin after activation of the Wnt/β- catenin signal transduction pathway.
Formation of stable complexes between two Alzheimer's disease gene products: Presenilin-2 and β-amyloid precursor protein
TLDR
It is shown that coexpression with PS2 resulted in a decrease of APP secretion, suggesting a direct participation of presenilins in the intracellular sorting, trafficking and processing of APP molecules.
Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis
TLDR
It is shown that presenilin-1 forms a complex with β-catenin in vivo that increases β-Catenin stability, which increases neuronal vulnerability to apoptosis induced by amyloid-β protein.
Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation*
TLDR
It is concluded that PS1 metabolism is highly controlled by multiple proteolytic activities indicating that subtle changes in fragment generation/degradation might be important for Alzheimer’s disease-associated pathology.
Participation of Presenilin 2 in Apoptosis: Enhanced Basal Activity Conferred by an Alzheimer Mutation
TLDR
A PS2 mutation associated with familial Alzheimer's disease was found to generate a molecule with enhanced basal apoptotic activity, which might accelerate the process of neurodegeneration that occurs in Alzheimer’s disease, leading to the earlier age of onset characteristic of familial Alzheimers disease.
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
TLDR
The results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.
Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing.
TLDR
The conservation of function of human PS-1 and C. elegans sel-12 suggests that presenilin proteins are required, directly or indirectly, for the proper operation of the Notch signalling pathway.
Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice
TLDR
The data demonstrate that the preseniiin mutations cause a dominant gain of function and may induce AD by enhancing Aβ42 production, thus promoting cerebral β-amyloidosis.
Presenilin Proteins Undergo Heterogeneous Endoproteolysis between Thr291and Ala299and Occur as Stable N- and C-Terminal Fragments in Normal and Alzheimer Brain Tissue
TLDR
The results indicate that presenilin polypeptides are rapidly processed to N- and C-terminal fragments in both neural and nonneural cells and that interference with this processing is not an obligatory feature of FAD-causing mutations.
Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease.
TLDR
In cells expressing PS2 containing the asparagine-141 FAD mutant, the ratio of alternative to normal PS2 cleavage fragments was increased relative to wild-type PS2-expressing cells, suggesting a potential role for apoptosis-associated cleavage of presenilins in the pathogenesis of Alzheimer's disease.
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