G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease-associated mutants of APP.
Missense mutations in the 695-amino acid form of the amyloid precursor protein (APP695) cosegregate with disease phenotype in families with dominantly inherited Alzheimer's disease. These mutations convert valine at position 642 to isoleucine, phenylalanine, or glycine. Expression of these mutant proteins, but not of normal APP695, was shown to induce nucleosomal DNA fragmentation in neuronal cells. Induction of DNA fragmentation required the cytoplasmic domain of the mutants and appeared to be mediated by heterotrimeric guanosine triphosphate-binding proteins (G proteins).
Yamatsuji
T
T
Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Matsui
T
T
Okamoto
T
T
Komatsuzaki
K
K
Takeda
S
S
Fukumoto
H
H
Iwatsubo
T
T
Suzuki
N
N
Asami-Odaka
A
A
Ireland
S
S
Kinane
T B
TB
Giambarella
U
U
Nishimoto
I
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017077:Culture Media, Conditioned; D004247:DNA / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D009707:Nucleosomes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D004247:DNA; D019204:GTP-Binding Proteins