Epigenetic contributions to symptom asymmetry in Parkinson's disease

表观遗传对帕金森病症状不对称的贡献

• 批准号: 10602454
• 负责人: Gerhard A Coetzee
• 金额: $ 44.65万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602454
• 关键词: 3-Dimensional; Acceleration; Affect; Age; Aging; Appearance; Bilateral; Biological; Brain; Brain Diseases; Cerebral hemisphere; Characteristics; Chromatin; Clinical; DNA Methylation; Data; Development; Disease; Disease Progression; Elderly; Epigenetic Process; Financial Hardship; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Health; Human; Impairment; Individual; Left; Link; Maps; Molecular; Molecular Profiling; Motor; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Outcome; Parkinson Disease; Pathology; Pathway Analysis; Patients; Pattern; Phenotype; Prefrontal Cortex; Prevalence; Process; Public Health; Regulator Genes; Research; Risk Factors; Role; Side; Structure; Subgroup; Symptoms; Synapses; Syndrome; Techniques; Work; advanced disease; alpha synuclein; epigenetic regulation; epigenome; epigenomics; genetic analysis; genome-wide; genome-wide analysis; improved; in vivo; insight; mind control; molecular asymmetry; motor symptom; neuron loss; neuropathology; nigrostriatal system; non-motor symptom; pre-clinical; progressive neurodegeneration; risk variant; transcriptome; transcriptomics

PROJECT SUMMARY Parkinson’s disease (PD) is a severe, irreversible neurodegenerative disease that involves asymmetric symptoms. For most patients (over 85%) motor symptoms begin on one side of the body. This motor asymmetry is so characteristic of PD that it is often used as a clinical parameter to differentiate PD from similar syndromes. Though motor symptoms gradually become bilateral as the disease progresses, the initial asymmetry remains stable and persists even at advanced disease stages. Lateralization in PD has been linked to rate of disease progression and differences in the presentation of non-motor symptoms, including cognitive symptoms. Symptom asymmetry in PD is the direct result of hemisphere differences in subcortical and cortical neuronal dysfunction and loss. Despite the prevalence of asymmetric brain changes in PD and its importance to clinical manifestations, the factors rendering neurons more vulnerable in one brain hemisphere over the other remain one the most enigmatic puzzles of PD. The goal of this study is to determine the molecular signatures enabling hemisphere differences in neuronal dysfunction and symptom asymmetry in PD. In PD, both the development of neuropathology and the progressive loss of neurons involve abnormalities in gene regulation. We have recently found evidence that hemisphere asymmetry in PD neurons involves differences in epigenetic marks that relate to transcriptional states. We have also found that neuronal epigenomes across hemispheres change with aging, a process that is accelerated in PD. Therefore, we propose that hemisphere differences in epigenetic regulation of genes could underlie the asymmetry in neuronal impairment, which in turn impacts symptom lateralization. This project involves cutting-edge techniques in epigenomics and adjoining transcriptomic and genetic analyses in isolated brain neurons of PD patients and controls. We also determine the impact of aging, rate of progression, and PD pathology on the development of hemisphere asymmetry. Our project will define (i) the extent of hemisphere asymmetry in the epigenome in neurons of PD patients, its effect on gene expression, and its relevance to symptom lateralization, (ii) the divergence of the epigenome across hemispheres with aging, and (iii) the capacity for PD neuropathology to induce epigenetic and transcriptional changes relevant to hemisphere asymmetry in vivo. This work will identify the genes involved in asymmetric neuronal dysfunction in PD. Uncovering the mechanisms involved in asymmetric brain changes in PD is important for understanding the biological basis of symptom lateralization in PD. This work also provides fundamental insight on the degree of molecular asymmetry across hemispheres of the human brain.

项目摘要 帕金森氏病（PD）是一种严重的，不可逆的神经退行性疾病，涉及不对称 症状。对于大多数患者（超过85％），运动症状从身体的一侧开始。这个电动机不对称 是PD的特征，以至于它通常用作将PD与类似综合症区分开的临床参数。 尽管随着疾病的发展，运动症状逐渐变得双侧，但最初的不对称性仍然存在 即使在晚期疾病阶段，稳定和持续也是如此。 PD中的横向化与疾病率有关 非运动症状（包括认知症状）的进展和差异。 PD中的症状不对称是皮质下和皮质神经元半球差异的直接结果 功能障碍和损失。尽管PD不对称大脑的发生率及其对临床的重要性 表现形式，使神经元在一个大脑半球上更脆弱的因素仍然存在 PD最神秘的难题之一。 这项研究的目的是确定能够在神经元中差异的分子特征 PD的功能障碍和症状不对称。在PD中，神经病理学的发展和进步 神经元的丧失涉及基因调节异常。我们最近发现了半球的证据 PD神经元中的不对称性涉及与转录状态有关的表观遗传标记的差异。我们有 还发现，跨半球的神经元表观人口统计随着衰老的变化而变化，这一过程被加速 PD。因此，我们提出，基因表观遗传调节的半球差异可能是 神经元影响的不对称性，进而影响症状横向化。 该项目涉及表观基因组学和相邻转录组学和遗传分析的尖端技术 在PD患者和对照组的孤立脑神经元中。我们还确定衰老的影响，进展速度， 和PD病理学关于半球不对称的发展。我们的项目将定义（i） PD患者神经元的表观基因组的半球不对称，其对基因表达的影响及其 与伴侣横向化相关，（ii）表观基因组在衰老的半球上的差异， （iii）PD神经病理学诱导与半球相关的表观遗传和转录变化的能力 体内不对称。这项工作将确定PD中涉及非对称神经元功能障碍的基因。 揭示PD不对称大脑变化涉及的机制对于理解 PD症状横向化的生物学基础。这项工作还提供了有关程度的基本见解 跨人脑半球的分子不对称。