Variants in Apaf-1 segregating with major depression promote apoptosome function.
APAF1, encoding the protein apoptosis protease activating factor 1 (Apaf-1), has recently been established as a chromosome 12 gene conferring predisposition to major depression in humans. The molecular phenotypes of Apaf-1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf-1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell. Cellular phenotypes were measured using a yeast heterologous expression assay in which human Apaf-1 and other proteins necessary to constitute a functional apoptotic pathway were overexpressed. Apaf-1 variants encoded by APAF1 alleles that segregate with major depression in families linked to chromosome 12 shared a common gain-of-function phenotype in both assay systems. In contrast, other Apaf-1 variants showed neutral or loss-of-function phenotypes. The depression-associated alleles thus have a common phenotype that is distinct from that of non-associated variants. This result suggests an etiologic role for enhanced apoptosis in major depression.
Harlan
J
J
Advanced Technologies, Abbott Laboratories, 100 Abbott Park Road R424/AP10, Abbott Park, IL 60064, USA.
Chen
Y
Y
Gubbins
E
E
Mueller
R
R
Roch
J-M
JM
Walter
K
K
Lake
M
M
Olsen
T
T
Metzger
P
P
Dorwin
S
S
Ladror
U
U
Egan
D A
DA
Severin
J
J
Johnson
R W
RW
Holzman
T F
TF
Voelp
K
K
Davenport
C
C
Beck
A
A
Potter
J
J
Gopalakrishnan
M
M
Hahn
A
A
Spear
B B
BB
Halbert
D N
DN
Sullivan
J P
JP
Abkevich
V
V
Neff
C D
CD
Skolnick
M H
MH
Shattuck
D
D
Katz
D A
DA
D000483:Alleles; D017209:Apoptosis / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1; D003865:Major Depressive Disorder / Q000235:genetics* / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins