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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：
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
项目类别：
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

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.

自闭症的线粒体-神经元假说摘要：自闭症是一种神经行为