一只 mtDNA 突变小鼠证明线粒体缺陷会导致自闭症内表型

An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotype

Keywords：ROS, Autism, Mitochondrial dysfunction 

关键词：活性氧，自闭症，线粒体功能障碍
作者：Tal Yardenia,, Ana G. Cristanchob, Almedia J. McCoy, Patrick M. Schaefera, Meagan J. McManusa,Eric D. Marshb,, and Douglas C. Wallacea

出版期刊：《Proc Natl Acad Sci U S A》 （2021/2/3）

Abstract：

Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations. 

文章摘要：

自闭症谱系障碍 (ASDs) 的特征是社交交流障碍、病理性重复行为、兴趣受限和脑电图 (EEG) 异常。虽然对核 DNA (nDNA) 变异的详尽分析揭示了数百个拷贝数变异 (CNV) 和功能丧失 (LOF) 突变，但尚未出现关于 ASD 病理生理学的统一假设。基于生化和生理分析，有人假设 ASD 可能是具有脑特异性表现的全身性线粒体缺陷的结果。这一提议得到了最近的线粒体 DNA (mtDNA) 分析的支持，该分析识别了 ASD 中的种系和体细胞 mtDNA 变体。如果线粒体缺陷确实易患 ASD，那么具有某些 mtDNA 突变的小鼠应该表现出自闭症内表型。为了检验这一预测，我们检测了一种携带 mtDNA ND6 基因错义突变 (P25L) 的小鼠品系。在没有减少海马中间神经元数量的情况下，这只老鼠表现出社交互动受损、重复行为和焦虑增加、脑电图改变和癫痫发作阈值降低。脑电图畸变在皮层最明显，其次是海马。线粒体呼吸功能和活性氧 (ROS) 水平的异常在皮质中最明显，其次是海马，但在嗅球中不存在。这些数据表明，轻度全身性线粒体缺陷可导致 ASD，而没有明显的神经解剖学缺陷，而全身性线粒体突变可导致组织特异性脑缺陷，并伴有区域神经生理学改变。

点击链接即可查看和下载文章：https://www.pnas.org/doi/full/10.1073/pnas.2021429118

文章题目、关键词与摘要译文仅用于参考。