Epigenetic contributions to symptom asymmetry in Parkinson's disease

项目总结 帕金森病(PD)是一种严重的、不可逆转的神经退行性疾病，涉及不对称 症状。对于大多数患者(超过85%)，运动症状开始于身体的一侧。这种马达不对称 是帕金森病的特征，常被用作区分帕金森病与类似证候的临床参数。 虽然随着疾病的进展，运动症状逐渐变成双侧，但最初的不对称仍然存在。 病情稳定，即使在疾病晚期也会持续存在。帕金森病的偏侧化与发病率有关 非运动症状的进展和差异，包括认知症状。 帕金森病的症状不对称是大脑皮质下神经元和皮质神经元大脑半球差异的直接结果 功能障碍和失落。尽管帕金森病患者普遍存在非对称性脑改变及其临床重要性 表现，使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 这是PD最神秘的谜题之一。 这项研究的目标是确定导致大脑半球神经元差异的分子特征。 帕金森病的功能障碍和症状不对称。在帕金森病中，神经病理学的发展和进行性 神经元的丢失与基因调控的异常有关。我们最近发现的证据表明大脑半球 帕金森病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，大脑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 警察。因此，我们认为半球在基因表观遗传调控上的差异可能是 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邻近的转录和遗传分析的尖端技术。 在帕金森病患者和对照组的分离脑神经元中。我们还确定了衰老的影响，进展率， 而帕金森病的病理基础是大脑半球不对称的发展。我们的项目将定义(I) 帕金森病患者神经细胞表观基因组半球不对称性及其对基因表达的影响 与症状偏侧化的相关性，(Ii)随着年龄的增长，表观基因组跨半球的差异，以及 (Iii)帕金森病神经病理导致与半球相关的表观遗传和转录变化的能力 体内的不对称性。这项工作将确定参与帕金森病不对称神经元功能障碍的基因。 揭示帕金森病患者大脑不对称变化的机制对于理解帕金森病 帕金森病症状偏侧化的生物学基础。这项工作还提供了对 人类大脑两个半球的分子不对称。

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.