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: 10403437
• 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/10403437
• 关键词: 3-Dimensional; 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; 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; 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.

项目概要 帕金森病 (PD) 是一种严重的、不可逆的神经退行性疾病，涉及不对称性 症状。对于大多数患者（超过 85%）来说，运动症状始于身体的一侧。这种运动不对称 它是帕金森病的特征，因此经常被用作区分帕金森病和类似综合征的临床参数。 尽管随着疾病的进展，运动症状逐渐变为双侧，但最初的不对称性仍然存在 即使在疾病晚期也能保持稳定和持续。 PD 的偏侧化与疾病发生率相关 非运动症状（包括认知症状）的进展和差异。 PD 症状不对称是半球皮质下和皮质神经元差异的直接结果 功能障碍和丧失。尽管帕金森病中脑部不对称变化很普遍及其对临床的重要性 表现中，导致一个大脑半球的神经元比另一个大脑半球更脆弱的因素仍然存在 PD 最神秘的谜题之一。 本研究的目的是确定导致半球神经元差异的分子特征 PD 中的功能障碍和症状不对称。在 PD 中，神经病理学的发展和进展 神经元的丧失涉及基因调控的异常。我们最近发现证据表明半球 PD神经元的不对称性涉及与转录状态相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基因组随着年龄的增长而变化，这一过程在 PD。因此，我们认为半球基因表观遗传调控的差异可能是 神经元损伤的不对称性，进而影响症状的偏侧化。 该项目涉及表观基因组学以及相关转录组学和遗传分析的尖端技术 在 PD 患者和对照组的分离脑神经元中。我们还确定衰老、进展速度的影响， 和 PD 病理学对半球不对称发展的影响。我们的项目将定义 (i) 的范围 PD患者神经元表观基因组半球不对称性及其对基因表达的影响及其研究 与症状偏侧化的相关性，（ii）随着年龄的增长，半球表观基因组的差异，以及 (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。这项工作将鉴定与帕金森病不对称神经元功能障碍有关的基因。 揭示帕金森病中大脑不对称变化的机制对于理解帕金森病的重要意义 PD 症状偏侧化的生物学基础。这项工作还提供了关于程度的基本见解 人脑半球的分子不对称。