Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia.
Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia.
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DOI：
10.1159/000441252
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Vawter MP
中科院分区：
文献类型：
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作者：
Hjelm BE;Rollins B;Mamdani F;Lauterborn JC;Kirov G;Lynch G;Gall CM;Sequeira A;Vawter MP
遗传证据支持这样的假设：精神分裂症（SZ）是一种由几个或多个基因功能破坏引起的多基因疾病。与SZ相关的最常见和可重复的细胞表型是新皮质内树突棘的减少，这表明树突结构的改变可能导致异常的皮质回路和SZ症状。在这里，我们回顾证据支持SZ病因学中线粒体功能障碍的多因素模型，并讨论这些线粒体功能障碍的多途径可能导致树突棘丢失和/或发育不全在一些SZ科目。SZ中线粒体功能障碍的病理生理作用是基于线粒体基因组和参与线粒体功能的核基因的基因组分析。先前的研究和初步数据表明SZ与线粒体基因组的特定等位基因和单倍型群相关，并且还与线粒体拷贝数的减少和线粒体DNA的同义和非同义替换的增加相关。线粒体功能障碍也被广泛牵连在SZ的全基因组关联，外显子组测序，改变基因表达，蛋白质组学，显微镜分析，诱导多能干细胞研究。总之，这些数据支持这一假设，SZ是一个多基因疾病与线粒体目标的富集。
Genetic evidence has supported the hypothesis that schizophrenia (SZ) is a polygenic disorder caused by the disruption in function of several or many genes. The most common and reproducible cellular phenotype associated with SZ is a reduction in dendritic spines within the neocortex, suggesting alterations in dendritic architecture may cause aberrant cortical circuitry and SZ symptoms. Here, we review evidence supporting a multifactorial model of mitochondrial dysfunction in SZ etiology and discuss how these multiple paths to mitochondrial dysfunction may contribute to dendritic spine loss and/or underdevelopment in some SZ subjects. The pathophysiological role of mitochondrial dysfunction in SZ is based upon genomic analyses of both the mitochondrial genome and nuclear genes involved in mitochondrial function. Previous studies and preliminary data suggest SZ is associated with specific alleles and haplogroups of the mitochondrial genome, and also correlates with a reduction in mitochondrial copy number and an increase in synonymous and nonsynonymous substitutions of mitochondrial DNA. Mitochondrial dysfunction has also been widely implicated in SZ by genome-wide association, exome sequencing, altered gene expression, proteomics, microscopy analyses, and induced pluripotent stem cell studies. Together, these data support the hypothesis that SZ is a polygenic disorder with an enrichment of mitochondrial targets.