A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM

自闭症的线粒体-神经元间质假说摘要：自闭症是一种神经行为 一种病因不明的疾病，每68名儿童中就有一名患病。我们假设导致自闭症的一个主要因素 谱系障碍(ASD)的风险是部分线粒体功能障碍导致神经元间抑制和 发育中的迁移缺陷。这导致大脑皮层神经元兴奋-抑制失衡。部分 线粒体功能障碍在ASD中被反复观察到。ASD患者的脑电异常表现为 可能是GABA能抑制中间神经元的来源。中间神经元能量旺盛，对 线粒体抑制和皮质兴奋-抑制失衡与ASD行为相关 异常现象。广泛的核DNA(NDNA)遗传学研究发现了多个与ASD相关的 单倍体不足的基因座，每个占少数病例，这意味着有超过1000个ASD基因座。这个 线粒体基因组由一到两千个nDNA基因加上数千个拷贝的 线粒体DNA(MtDNA)，因此部分线粒体功能障碍可由nDNA单倍体不足或 有害的线粒体DNA变异。我们已经证明了许多与ASD相关的nDNA单倍体不足变体 影响线粒体功能，某些线粒体DNA谱系(单倍群)与ASD风险相关，即 ASD相关mtDNALeu(UUR)nt3243A&gt；G突变导致线粒体功能障碍 多个ASD nDNA基因的表达，氧磷脂的化学和遗传抑制影响中间神经元 皮质发育迁移，携带轻度mtDNA突变的小鼠表现出ASD相关 包括脑电异常在内的内表型。进一步检测线粒体缺陷-神经元间质失衡 假设我们提出了三个具体目标。首先，我们将确定ASD患者的mtdna序列 以及使用非靶标外显子序列数据或直接mtDNA测序并关联mtDNA的对照 具有自闭症风险的单倍群和最近的有害突变。然后将分析与ASD相关的mtDNA 针对传递线粒体囊体内的线粒体功能障碍。其次，我们将分析16p11.2 CNV ASD 线粒体功能障碍和转录谱改变的细胞系，并将结果与ASD进行比较 线粒体DNA亮氨酸(UUR)nt3243A和gt；G胞体。然后我们将确定mtdna变异如何影响临床变异性。 与16p11.2 CNV相关。最后，我们将确定神经元间特异性ndna的作用。 线粒体基因和系统性mtDNA基因缺陷对皮质神经元间发育迁移的影响 ASD内表型和社会行为异常的相关表现。小鼠带有 内表型但非显性ASD样行为将暴露于聚(I：C)诱导的宫内炎症 确定他们是否更容易诱发类似ASD的行为。如果通过这些实验验证，我们的 线粒体缺陷-神经元间失衡假说实际上可以涵盖所有不同的 与ASD相关的观察。

A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM Abstract: Autism is a neurobehavioral disorder of unknown etiology that affects one in 68 children. We hypothesize that a major contributor to autism spectrum disorder (ASD) risk is partial mitochondrial dysfunction causing interneuron inhibition and developmental migration defects. This results in cortical neuronal excitation-inhibition imbalance. Partial mitochondrial dysfunction has been repeatedly observed in ASD. ASD patients exhibit EEG abnormalities of likely GABAergic inhibitory interneuron origin. Interneurons are highly energetic and acutely sensitive to mitochondrial inhibition and cortical excitation-inhibition imbalance is associated with ASD behavioral abnormalities. Extensive nuclear DNA (nDNA) genetic studies have identified multiple ASD-associated haploinsufficient loci, each accounting for a few cases, implying that there are over a thousand ASD loci. The mitochondrial genome consists of between one and two thousand nDNA genes plus thousands of copies of the mitochondrial DNA (mtDNA), so partial mitochondrial dysfunction can result from nDNA haploinsufficiency or deleterious mtDNA variants. We have shown that many ASD-associated nDNA haploinsufficiency variants affect mitochondrial functions, that certain mtDNA lineages (haplogroups) correlate with ASD-risk, that the ASD-associated mtDNALeu(UUR) nt 3243A>G mutation results in mitochondrial dysfunction and perturbation of expression of multiple ASD nDNA genes, that chemical and genetic inhibition of OXPHOS impacts interneuron cortical developmental migration, and that mice harboring mild mtDNA mutants exhibit ASD-associated endophenotypes including EEG abnormalities. To further test the mitochondrial defect-interneuron imbalance hypothesis we propose three specific aims. First, we will determine the mtDNA sequences of ASD patients and controls using off-target exome sequence data or direct mtDNA sequencing and correlate the mtDNA haplogroups and recent deleterious mutations with ASD risk. ASD-associated mtDNAs will then be analyzed for mitochondrial dysfunction within transmitochondrial cybrids. Second, we will analyze 16p11.2 CNV ASD cell lines for mitochondrial dysfunction and altered transcription profiles and compare the results to ASD mtDNALeu(UUR) nt 3243A>G cybrids. We will then determine how mtDNA variation affects the clinical variability associated with 16p11.2 CNVs. Finally, we will determine the effect of interneuron-specific nDNA mitochondrial gene and systemic mtDNA gene defects on cortical interneuron developmental migration and associated manifestation of ASD endophenotypes and social-behavioral aberrations. Mice with endophenotypes but non-overt ASD-like behavior will be exposed to poly (I:C)-induced in utero inflammation to determine if they are more prone to induction of ASD-like behavior. If validated by these experiments our mitochondrial defect-interneuron imbalance hypothesis can encompass virtually all of the disparate observations associated with ASD.