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Variants in Apaf-1 segregating with major depression promote apoptosome function.

Abstract：

: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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Harlan J,Chen Y,Gubbins E,Mueller R,Roch JM,Walter K,Lake M,Olsen T,Metzger P,Dorwin S,Ladror U,Egan DA,Severin J,Johnson RW,Holzman TF,Voelp K,Davenport C,Beck A,Potter J,Gopalakrishnan M,Hahn A,Spear BB,Halb

doi

10.1038/sj.mp.4001755

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

76-85

issue

1

eissn

1359-4184

issn

1476-5578

pii

4001755

journal_volume

11

pub_type

杂志文章

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