Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.
Overexpression of the familial Alzheimer's disease gene Presenilin 2 (PS2) in nerve growth factor-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or beta-amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in nerve growth factor-differentiated or amyloid precursor protein-expressing PC12 cells. The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins are involved. A PS2 mutation associated with familial Alzheimer's disease was found to generate a molecule with enhanced basal apoptotic activity. This gain of function might accelerate the process of neurodegeneration that occurs in Alzheimer's disease, leading to the earlier age of onset characteristic of familial Alzheimer's disease.
Wolozin
B
B
Unit on Alzheimer Biology, Laboratory of Clinical Science, National Institute of Mental Health, Building 10, Room 3D41, 9000 Rockville Pike, Bethesda, MD 20892, USA. ldadamio@atlas.niaid.nih.gov
Iwasaki
K
K
Vito
P
P
Ganjei
J K
JK
Lacanà
E
E
Sunderland
T
T
Zhao
B
B
Kusiak
J W
JW
Wasco
W
W
D'Adamio
L
L
D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016373:DNA, Antisense / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin; D053766:Presenilin-2; D051381:Rats; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C094559:APP717; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016373:DNA, Antisense; D008565:Membrane Proteins; D009414:Nerve Growth Factors; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D010566:Virulence Factors, Bordetella; C075222:amyloid beta-protein (1-42); D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs