Molecular signatures of Parkinsons disease in the gut and brain

肠道和大脑中帕金森病的分子特征

• 批准号: 9804994
• 负责人: Patrik Brundin
• 金额: $ 52.25万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9804994
• 关键词: Acceleration; Affect; Age; Aging; Anatomy; Appendectomy; Autophagocytosis; Biological; Brain; Brain Diseases; Brain region; Cleaved cell; DNA Methylation; Data; Databases; Development; Diagnostic; Disease Progression; Elderly; Enteral; Epigenetic Process; Etiology; Excision; Exhibits; Functional disorder; Gastrointestinal tract structure; Genes; Genetic Fingerprintings; Genetic Transcription; Goals; Human; Impairment; In Vitro; Individual; Investigation; Lewy Bodies; Link; Maps; Mediating; Mission; Modification; Molecular Profiling; Motor; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Onset of illness; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathological Staging; Pathology; Pathway interactions; Patients; Pattern; Play; Public Health; Recombinants; Regulation; Reporting; Research; Risk; Risk Factors; Role; Substantia nigra structure; System; Testing; Therapeutic; Travel; United States National Institutes of Health; Work; age related; alpha synuclein; dopaminergic neuron; epidemiology study; epigenetic regulation; gastrointestinal; genome wide association study; insight; misfolded protein; motor disorder; motor symptom; neurotoxic; non-motor symptom; predictive marker; retrograde transport; transcriptome; transcriptomics

Project Summary Parkinson’s disease (PD) is a devastating neurodegenerative disease characterized by motor and non-motor symptoms and a specific pathology that may originate in the gastrointestinal (GI) tract. PD pathology in the brain involves neurotoxic aggregates of alpha-synuclein and the loss of dopaminergic neurons in the substantia nigra. In the GI tract, similar alpha-synuclein pathology has been detected, even years before motor symptom onset. There is also evidence that alpha-synuclein aggregates travel via the vagal nerve from the gut to the brain, and pathological staging of the PD brain supports a GI origin. As such, pathogenic alpha-synuclein originating from the GI tract is thought to spread to the brain via vagal retrograde transport to induce nigral neurodegeneration and PD. However, what facilitates the accumulation and spread of alpha-synuclein pathology in the gut is still unknown. In this study, we ask: what are the molecular signatures in the GI tract of PD patients that enable the spread of alpha-synuclein pathology to the brain? We recently found that alpha-synuclein pathology was prevalent in the human vermiform appendix in both healthy and PD individuals. Our study demonstrated that (i) the appendix is a reservoir for pathogenic forms of alpha-synuclein and (ii) removal of the appendix substantially reduced the risk for developing PD. Importantly, this work indicates that PD and healthy individuals must differ in their ability to manage alpha-synuclein pathology. We hypothesize that a crucial difference between the PD and healthy appendix is in the control of the autophagy-lysosomal pathway – a key pathway that mediates the degradation and spread of pathogenic alpha-synuclein. Epigenetic marks like DNA methylation effectively regulate the activity of genes in the autophagy-lysosomal pathway and is involved in the decline of autophagy with age. Our data shows that in neurons of PD brains, DNA methylation abnormalities indeed occur at autophagy-lysosomal genes, along with their transcriptional dysregulation. In this study, we will now determine whether DNA methylation abnormalities at autophagy- lysosomal genes occur in the appendix of PD patients. We will map DNA methylation at autophagy-lysosomal genes (n=665) and perform a transcriptomic investigation the PD appendix. We will also determine whether DNA methylation perturbations at autophagy-lysosomal genes are mirrored in the PD appendix and brain. Next, we will determine the age-dependent regulation of autophagy-lysosomal genes in the appendix, and whether PD patients show altered epigenetic and transcriptional patterns of aging at these genes. Together, our study will provide new insights on the mechanisms underlying alpha-synuclein abnormalities in the PD gut and pathological progression in the brain. This work will be formative for the development of early PD diagnostics and treatments directed to the accessible GI tract.

项目概要 帕金森病（PD）是一种破坏性的神经退行性疾病，其特征是运动和非运动 可能起源于胃肠道 (GI) 的症状和特定病理。脑部 PD 病理学 涉及神经毒性聚集的α-突触核蛋白和黑质中多巴胺能神经元的损失。 在胃肠道中，甚至在运动症状出现前数年，就已经检测到类似的α-突触核蛋白病理。 还有证据表明 α-突触核蛋白聚集体通过迷走神经从肠道到达大脑，并且 PD 大脑的病理分期支持胃肠道起源。因此，致病性 α-突触核蛋白源自 胃肠道被认为通过迷走神经逆行运输扩散到大脑，从而诱发黑质神经变性和帕金森病。 然而，是什么促进了α-突触核蛋白病理学在肠道中的积累和传播仍然未知。 在这项研究中，我们要问：帕金森病患者胃肠道中有哪些分子特征能够促进帕金森病的传播？ α-突触核蛋白对大脑的病理学影响？我们最近发现 α-突触核蛋白病理学在 健康和帕金森病个体的人类蚓状阑尾。我们的研究表明 (i) 附录是 α-突触核蛋白致病形式的储存库和（ii）阑尾的切除大大减少了 发生帕金森病的风险。重要的是，这项工作表明 PD 和健康个体的能力肯定有所不同 管理α-突触核蛋白病理学。我们假设 PD 和健康人之间的一个关键区别 阑尾控制着自噬-溶酶体途径——介导降解的关键途径 和致病性α-突触核蛋白的传播。 DNA甲基化等表观遗传标记有效调节自噬-溶酶体中基因的活性 途径并参与自噬随年龄的下降。我们的数据显示，在帕金森病大脑的神经元中，DNA 甲基化异常确实发生在自噬溶酶体基因及其转录上 失调。在这项研究中，我们现在将确定自噬过程中 DNA 甲基化是否异常。 溶酶体基因存在于 PD 患者的阑尾中。我们将绘制自噬-溶酶体 DNA 甲基化图谱 基因 (n=665) 并对 PD 阑尾进行转录组学研究。我们还将确定 DNA 是否 自噬溶酶体基因的甲基化扰动反映在 PD 阑尾和大脑中。接下来，我们 将决定阑尾中自噬溶酶体基因的年龄依赖性调节，以及 PD 是否 患者在这些基因上表现出改变的表观遗传和衰老转录模式。我们的研究将共同 为 PD 肠道和病理学中 α-突触核蛋白异常的机制提供新见解 大脑中的进展。这项工作将对早期帕金森病诊断和治疗的发展产生影响 引导至可到达的胃肠道。