Variants in Apaf-1 segregating with major depression promote apoptosome function
2005; Springer Nature; Volume: 11; Issue: 1 Linguagem: Inglês
10.1038/sj.mp.4001755
ISSN1476-5578
AutoresJohn E. Harlan, Y Chen, Earl J. Gubbins, Reinhold Mueller, J-M Roch, Katharina Walter, Marc Lake, Timothy W. Olsen, Péter Metzger, Sarah A. Dorwin, Uri S. Ladror, David A. Egan, Jean M. Severin, R.W. Johnson, Thomas F. Holzman, K Voelp, C Davenport, Audrey Beck, Jennifer Potter, Murali Gopalakrishnan, Alfred Hahn, B B Spear, Donald N. Halbert, J P Sullivan, Victor Abkevich, Chris Neff, Mark H. Skolnick, Donna Shattuck, David A. Katz,
Tópico(s)Endoplasmic Reticulum Stress and Disease
ResumoAPAF1, 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.
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