PUBLICATION
Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta-peptide production and requires a critical aspartate residue for its function in amyloidogenesis
- Authors
- Leimer, U., Lun, K., Romig, H., Walter, J., Grunberg, J., Brand, M., and Haass, C.
- ID
- ZDB-PUB-991102-23
- Date
- 1999
- Source
- Biochemistry 38(41): 13602-13609 (Journal)
- Registered Authors
- Brand, Michael, Lun, Klaus
- Keywords
- protein synthesis; Alzheimer disease; amyloid beta protein; presenilin 1; presenilin 2; aspartic acid
- MeSH Terms
-
- Alzheimer Disease/genetics
- Alzheimer Disease/metabolism
- Alzheimer Disease/pathology
- Amino Acid Sequence
- Amyloid beta-Peptides/biosynthesis*
- Amyloid beta-Peptides/genetics
- Animals
- Aspartic Acid/chemistry
- Aspartic Acid/physiology*
- Cell Line
- Conserved Sequence
- Embryonic and Fetal Development/genetics
- Female
- Humans
- Membrane Proteins/biosynthesis
- Membrane Proteins/chemistry
- Membrane Proteins/genetics
- Membrane Proteins/physiology*
- Molecular Sequence Data
- Mutagenesis, Site-Directed
- Peptide Fragments/biosynthesis*
- Peptide Fragments/genetics
- Presenilin-1
- Protein Processing, Post-Translational
- Sequence Analysis, Protein
- Sequence Homology, Amino Acid
- Transfection
- Zebrafish
- PubMed
- 10521267 Full text @ Biochemistry
Citation
Leimer, U., Lun, K., Romig, H., Walter, J., Grunberg, J., Brand, M., and Haass, C. (1999) Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta-peptide production and requires a critical aspartate residue for its function in amyloidogenesis. Biochemistry. 38(41):13602-13609.
Abstract
Alzheimer's disease (AD) is characterized by the invariable accumulation of senile plaques composed of amyloid beta-peptide (Abeta). Mutations in three genes are known to cause familial Alzheimer's disease (FAD). The mutations occur in the genes encoding the beta-amyloid precursor protein (betaAPP) and presenilin (PS1) and PS2 and cause the increased secretion of the pathologically relevant 42 amino acid Abeta42. We have now cloned the zebrafish (Danio rerio) PS1 homologue (zf-PS1) to study its function in amyloidogenesis and to prove the critical requirement of an unusual aspartate residue within the seventh putative transmembrane domain. In situ hybridization and reverse PCR reveal that zf-PS1 is maternally inherited and ubiquitously expressed during embryogenesis, suggesting an essential housekeeping function. zf-PS1 is proteolytically processed to produce a C-terminal fragment (CTF) of approximately 24 kDa similar to human PS proteins. Surprisingly, wt zf-PS1 promotes aberrant Abeta42 secretion like FAD associated human PS1 mutations. The unexpected pathologic activity of wt zf-PS1 may be due to several amino acid exchanges at positions where FAD-associated mutations have been observed. The amyloidogenic function of zf-PS1 depends on the conserved aspartate residue 374 within the seventh putative transmembrane domain. Mutagenizing this critical aspartate residue abolishes endoproteolysis of zf-PS1 and inhibits Abeta secretion in human cells. Inhibition of Abeta secretion is accompanied by the accumulation of C-terminal fragments of betaAPP, suggesting a defect in gamma-secretase activity. These data provide further evidence that PS proteins are directly involved in the proteolytic cleavage of betaAPP and demonstrate that this function is evolutionarily conserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping