Variants in Apaf-1 segregating with major depression promote apoptosome function
| Autor: | D A Egan, P Metzger, Jennifer Potter, Yuan Chen, S Dorwin, M Gopalakrishnan, J P Sullivan, Chris Neff, A Hahn, M Lake, Donna Shattuck, Karl A. Walter, R Mueller, Victor Abkevich, T Olsen, Audrey Beck, T. F. Holzman, B B Spear, Mark H. Skolnick, Jean M. Severin, J.E. Harlan, R W Johnson, C Davenport, E. Gubbins, K Voelp, David A. Katz, J-M Roch, U.S. Ladror, D N Halbert |
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| Rok vydání: | 2005 |
| Předmět: |
Caspase-9
Genetics Depressive Disorder Major Polymorphism Genetic biology Intracellular Signaling Peptides and Proteins Proteins Apoptosis Phenotype Cellular and Molecular Neuroscience Psychiatry and Mental health Apoptotic Protease-Activating Factor 1 biology.protein Humans Genetic Predisposition to Disease Apoptosome APAF1 Heterologous expression Allele Molecular Biology Gene Alleles Chromosome 12 |
| Zdroj: | Molecular Psychiatry. 11:76-85 |
| ISSN: | 1476-5578 1359-4184 |
| DOI: | 10.1038/sj.mp.4001755 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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