G protein betagamma complex-mediated apoptosis by familial Alzheimer's disease mutant of APP.
In familial Alzheimer's disease (FAD), three missense mutations, V642I, V642F and V642G, that co-segregate with the disease phenotype have been discovered in the 695 amino acid form of the amyloid precursor protein APP. Expression of these mutants causes a COS cell NK1 clone to undergo pertussis toxin-sensitive apoptosis in an FAD trait-linked manner by activating the G protein Go, which consists of G alpha(o) and G betagamma subunits. We investigated which subunit was responsible for the induction of apoptosis by V642I APP in NK1 cells. In the same system, expression of mutationally activated G alpha(o) or G alpha(i) induced little apoptosis. Apoptosis by V642I APP was antagonized by the overexpression of the carboxy-terminal amino acids 495-689 of the beta-adrenergic receptor kinase-1, which blocks the specific functions of G betagamma. Co-transfection of G beta2gamma2 cDNAs, but not that of other G beta(x)gamma(z) (x = 1-3; z = 2, 3), induced DNA fragmentation in a manner sensitive to bcl-2. These data implicate G betagamma as a cell death mediator for the FAD-associated mutant of APP.
Giambarella
U
U
Department of Pharmacology and Neurosciences, Keio University School of Medicine, Tokyo, Japan.
Yamatsuji
T
T
Okamoto
T
T
Matsui
T
T
Ikezu
T
T
Murayama
Y
Y
Levine
M A
MA
Katz
A
A
Gautam
N
N
Nishimoto
I
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D019556:COS Cells; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D053938:DNA Fragmentation; D018076:DNA, Complementary; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019254:Genes, bcl-2; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D037342:Pertussis Toxin; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D051552:beta-Adrenergic Receptor Kinases
D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D010446:Peptide Fragments; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins