Presenilin-1 is processed into two major cleavage products in neuronal cell lines.
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.
Ward
R V
RV
Department of Molecular Neuropathology, Smithkline Beecham Pharmaceuticals, Harlow, Essex, UK.
Davis
J B
JB
Gray
C W
CW
Barton
A J
AJ
Bresciani
L G
LG
Caivano
M
M
Murphy
V F
VF
Duff
K
K
Hutton
M
M
Hardy
J
J
Roberts
G W
GW
Karran
E H
EH
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
D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1