A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM

自闭症的线粒体-神经元假说

基本信息

批准号：
9175487
负责人：
Douglas C Wallace
金额：
$ 67.33万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9175487
关键词：
16p11.2 Accounting Adenine Nucleotides Affect Autistic Disorder Behavior Behavioral Bioenergetics Body Weight Brain Cell Line Cells Child Clinical Collection Complex Copy Number Polymorphism DNA DNA Sequence Data Defect Development Electroencephalography Electrophysiology (science)Equilibrium Etiology Exhibits Family Functional disorder Gene Mutation Genes Genetic Genetic Transcription Genetic Variation Genetic study Glutamates Haplogroup Hippocampus (Brain)Inflammation Inherited Interneuron function Interneurons Leucine-Specific tRNA Life Mitochondria Mitochondrial DNA Modeling Mus Mutation Neurons Nuclear Nucleotides Oxidative Phosphorylation Oxygen Parvalbumins Patients Physiological Poly I-C Predisposition Protein Isoforms Reporting Risk Factors Role Slice Sum Testing Variant abstracting autism spectrum disorder chemical genetics disorder risk endophenotype exome sequencing 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 research study social

项目摘要

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.

自闭症摘要的线粒体interneronal假说：自闭症是神经行为未知病因的障碍会影响68个儿童中的一个。我们假设自闭症的主要贡献者频谱障碍（ASD）风险是部分线粒体功能障碍，导致中间神经元抑制和发展迁移缺陷。这会导致皮质神经元激发抑制失衡。部分的在ASD中反复观察到线粒体功能障碍。 ASD患者表现出脑电图异常可能的GABA能抑制性中间神经元起源。中间神经元具有高能量，对线粒体抑制和皮质激发抑制不平衡与ASD行为有关异常。广泛的核DNA（NDNA）遗传研究已经确定了多个与ASD相关的单倍宽松的基因座，每种基因座，占几种情况，这意味着有一千多个ASD基因座。这线粒体基因组由一到两千个NDNA基因以及数千份线粒体DNA（mtDNA），因此nDNA单倍氨基性或有害mtdna变体。我们已经表明，许多与ASD相关的NDNA单倍性变体影响线粒体功能，某些mtDNA谱系（单倍群）与ASD风险相关，即与ASD相关的mtdnaleu（Uur）NT 3243A> g突变导致线粒体功能障碍和扰动多个ASD NDNA基因的表达，化学和遗传抑制Oxphos会影响中间神经元皮质发育迁移，携带轻度mtDNA突变体的小鼠表现出ASD相关的内表型，包括脑电图异常。进一步测试线粒体缺陷 - interneuron不平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序列以及使用脱靶外显子组序列数据或直接mtDNA测序的对照并将mtDNA关联单倍群和最近具有ASD风险的有害突变。然后将分析与ASD相关的MTDNA 对于多脊髓软骨囊状内部的线粒体功能障碍。其次，我们将分析16p11.2 CNV ASD 线粒体功能障碍和转录轮廓改变的细胞系，并将结果与ASD进行比较 mtdnaleu（uur）nt 3243a> g cybrids。然后，我们将确定mtDNA变异如何影响临床变异性与16p11.2 CNV相关联。最后，我们将确定间神经特异性nDNA的效果线粒体基因和全身mtDNA基因缺陷在皮质间神经元发育和 ASD内表型和社会行为畸变的相关表现。老鼠与内表型，但非反过来的ASD样行为将暴露于子宫炎症中诱导的poly（i：c）确定它们是否更容易引起类似ASD的行为。如果通过这些实验来验证我们的线粒体缺陷interneuron不平衡假设几乎可以包含所有不同的与ASD相关的观察结果。