Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch.
Most of the genetically inherited Alzheimer's disease cases are caused by mutations in the presenilin genes, PS1 and PS2. PS mutations result in the enhanced production of the highly amyloidogenic 42/43 amino acid variant of amyloid beta-peptide (Abeta). We have introduced arbitrary mutations at position 286 of PS1, where a naturally occurring PS1 mutation has been described (L286V). Introduction of charged amino acids (L286E or L286R) resulted in an increase of Abeta42/43 production, which reached almost twice the level of the naturally occurring PS1 mutation. Although pathological Abeta production was increased, endoproteolysis of Notch and nuclear transport of its cytoplasmic domain was significantly inhibited. These results demonstrate that the biological function of PS proteins in the endoproteolysis of beta-amyloid precursor protein and Notch can be separated.
Kulic
L
L
Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's Disease Research, Ludwig Maximilians University, 80336 Munich, Germany.
Walter
J
J
Multhaup
G
G
Teplow
D B
DB
Baumeister
R
R
Romig
H
H
Capell
A
A
Steiner
H
H
Haass
C
C
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics; D002478:Cells, Cultured; D003062:Codon / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D051880:Receptors, Notch; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003062:Codon; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051880:Receptors, Notch