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

• DOI: 10.1038/sj.mp.4001755
• Publication Date: 2005-10-18T11:04:37Z
• Authors: J Harlan; Y Chen; E Gubbins; R Mueller; J-M Roch; K Walter; M Lake; T Olsen; P Metzger; S Dorwin; U Ladror; D A Egan; J Severin; R W Johnson; T F Holzman; K Voelp; C Davenport; A Beck; J Potter; M Gopalakrishnan; A Hahn; B B Spear; D N Halbert; J P Sullivan; V Abkevich; C D Neff; M H Skolnick; D Shattuck; D A Katz
• Keywords: Apoptosome; Loss 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.