title: Presenilin-1 is processed into two major cleavage products in neuronal cell lines.
abstract: Presenilin-1 (PS-1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). Using PS-1 transfected SHSY5Y neuroblastoma cells, we have demonstrated by immunodetection, using polyclonal antibodies, that PS-1 is processed to give two fragments: an N-terminal 28 kDa fragment, and a C-terminal 18 kDa fragment. In a number of non-transfected cell types, most PS-1 is detected as the cleaved products. The molecular weights of the PS-1 cleavage products suggest that the cleavage point will most probably be within a region of the hydrophilic loop domain coded for by either exon 8 or 9 of the PS-1 gene. The clustering of FAD mutations within exon 8 strongly suggests that it encodes a key functional domain. It seems likely that the cleavage of PS-1 is crucial to some aspect of its functionality. An understanding of this process will give insights into the pathology of AD, and may offer new opportunities for therapeutic intervention.
authors.affiliation: Department of Molecular Neuropathology, Smithkline Beecham Pharmaceuticals, Harlow, Essex, UK.
authors.forename: R V
authors.initials: RV
authors.lastname: Ward
authors.forename: J B
authors.initials: JB
authors.lastname: Davis
authors.forename: C W
authors.initials: CW
authors.lastname: Gray
authors.forename: A J
authors.initials: AJ
authors.lastname: Barton
authors.forename: L G
authors.initials: LG
authors.lastname: Bresciani
authors.forename: M
authors.initials: M
authors.lastname: Caivano
authors.forename: V F
authors.initials: VF
authors.lastname: Murphy
authors.forename: K
authors.initials: K
authors.lastname: Duff
authors.forename: M
authors.initials: M
authors.lastname: Hutton
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.forename: G W
authors.initials: GW
authors.lastname: Roberts
authors.forename: E H
authors.initials: EH
authors.lastname: Karran
mesh_terms: D000595:Amino Acid Sequence; D005091:Exons; D005796:Genes; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1