A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM

自闭症的线粒体-神经元假说

• 批准号: 9927676
• 负责人: Douglas C Wallace
• 金额: $ 60.6万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927676
• 关键词: 16p11.2; Accounting; Acute; Adenine Nucleotides; Affect; Behavior; Behavior Disorders; Behavioral; Bioenergetics; Body Weight; Brain; Cell Line; Cells; Child; Clinical; Collection; Complex; Copy Number Polymorphism; DNA; DNA Sequence; DNA sequencing; Data; Defect; Development; Electroencephalography; Electrophysiology (science); Equilibrium; Etiology; Exhibits; Exposure to; Family; Functional disorder; Gene Mutation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genetic study; Glutamates; Haplogroup; Hippocampus (Brain); Impairment; Inflammation; Inherited; Interneuron function; Interneurons; Leucine-Specific tRNA; Mitochondria; Mitochondrial DNA; Modeling; Mus; Mutation; Mutation Analysis; Neurons; Nuclear; Nucleotides; Oxidative Phosphorylation; Oxygen; Parvalbumins; Pathogenicity; Patients; Physiological; Poly I-C; Predisposition; Protein Isoforms; Reporting; Risk Factors; Role; Slice; Sum; Testing; Transcription Alteration; Variant; autism spectrum disorder; chemical genetics; disorder risk; endophenotype; exome; exome sequencing; experimental study; genetic analysis; genetic pedigree; genome wide association study; hippocampal pyramidal neuron; in utero; loss of function mutation; migration; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; mouse model; mutant; neurobehavioral disorder; patch clamp; social; virtual

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.

自闭症的线粒体-神经元假说 摘要：自闭症是一种神经行为 病因不明的疾病影响六十八名儿童中的一名。我们假设自闭症的一个主要原因 谱系障碍 (ASD) 风险是部分线粒体功能障碍导致中间神经元抑制和 发育迁移缺陷。这导致皮质神经元兴奋抑制失衡。部分的 在 ASD 中反复观察到线粒体功能障碍。自闭症谱系障碍 (ASD) 患者的脑电图异常 可能是 GABA 能抑制性中间神经元起源。中间神经元精力充沛且对 线粒体抑制和皮质兴奋抑制失衡与 ASD 行为相关 异常。广泛的核 DNA (nDNA) 遗传学研究已发现多种与 ASD 相关的基因 单倍体基因座不足，每个基因座占几个病例，这意味着自闭症谱系障碍基因座有一千多个。这 线粒体基因组由一到两千个 nDNA 基因加上数千个拷贝组成 线粒体 DNA (mtDNA)，因此部分线粒体功能障碍可能是由于 nDNA 单倍体不足或 有害的线粒体DNA变异。我们已经证明许多与 ASD 相关的 nDNA 单倍体不足变异 影响线粒体功能，某些 mtDNA 谱系（单倍群）与 ASD 风险相关， ASD 相关 mtDNALeu(UUR) nt 3243A>G 突变导致线粒体功能障碍和线粒体功能紊乱 多个 ASD nDNA 基因的表达，OXPHOS 的化学和遗传抑制会影响中间神经元 皮层发育迁移，并且携带轻度 mtDNA 突变体的小鼠表现出与 ASD 相关的 内表型，包括脑电图异常。进一步测试线粒体缺陷-中间神经元失衡 假设我们提出三个具体目标。首先，我们将确定ASD患者的mtDNA序列 使用脱靶外显子组序列数据或直接 mtDNA 测序进行对照，并将 mtDNA 关联起来 单倍群和最近具有 ASD 风险的有害突变。然后将分析 ASD 相关 mtDNA 用于传输软骨细胞内的线粒体功能障碍。其次，我们来分析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 mtDNALeu(UUR) nt 3243A>G 杂种。然后我们将确定 mtDNA 变异如何影响临床变异 与 16p11.2 CNV 相关。最后，我们将确定中间神经元特异性 nDNA 的影响 线粒体基因和全身 mtDNA 基因缺陷对皮质中间神经元发育迁移和 ASD 内表型和社会行为失常的相关表现。小鼠与 内表型但非明显的 ASD 样行为将暴露于聚 (I:C) 诱导的子宫内炎症中 确定他们是否更容易诱发自闭症谱系障碍 (ASD) 样行为。如果通过这些实验验证我们的 线粒体缺陷-中间神经元失衡假说几乎涵盖了所有不同的 与 ASD 相关的观察结果。

项目成果

Mitochondrial genetic medicine.

线粒体遗传医学。

• 发表时间: 2018
• 影响因子: 30.8
• 作者: Wallace; Douglas C
• 通讯作者: Douglas C

Mitochondrial mutations alter endurance exercise response and determinants in mice.

线粒体突变改变小鼠的耐力运动反应和决定因素。

• 发表时间: 2022-05-03
• 影响因子: 11.1
• 作者: Schaefer, Patrick M;Rathi, Komal;Butic, Arrienne;Tan, Wendy;Mitchell, Katherine;Wallace, Douglas C
• 通讯作者: Wallace, Douglas C