The contribution of the vermiform appendix to Parkinson's disease

蚓状阑尾对帕金森病的贡献

• 批准号: 10427267
• 负责人: Lena Cecilia Brundin
• 金额: $ 45.92万
• 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: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427267
• 关键词: Advanced Development; Affect; Age; Anatomy; Autophagocytosis; Biochemical; Biological; Biological Assay; Brain; Brain Diseases; Brain Pathology; Cecum; DNA Methylation; Data; Development; Digestive System Disorders; Early Diagnosis; Enteral; Epigenetic Process; Etiology; Excision; Exhibits; Experimental Models; Functional disorder; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Gold; Human; Individual; Lead; Lewy Bodies; Maps; Mass Spectrum Analysis; Mission; Molecular; Molecular Profiling; Motor; Mus; National Institute of Neurological Disorders and Stroke; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Patients; Process; Proteins; Regulator Genes; Research; Resources; Risk; Seeds; Shapes; Source; Substantia nigra structure; System; Testing; Therapeutic Intervention; Tissues; United States National Institutes of Health; Wild Type Mouse; Work; alpha synuclein; disease diagnostic; disorder control; dopaminergic neuron; epidemiology study; epigenetic profiling; experimental study; gastrointestinal; genome-wide; gut inflammation; in vivo; innovation; insight; motor disorder; motor symptom; neuropathology; non-motor symptom; predictive marker; programmed cell death protein 1; synucleinopathy; therapy development; tool; transcriptomics

Parkinson's disease (PD) is a devastating neurodegenerative disease characterized by motor and non-motor symptoms. The hallmark pathology of PD in the brain is the presence of alpha-synuclein (α-syn) aggregates, along with the loss of dopaminergic neurons in the substantia nigra. The brain α-syn pathology is thought to start in the gastrointestinal (GI) tract, since both GI dysfunction and the presence of α-syn aggregates in the GI tract usually precede motor symptoms by many years. In addition, experimental models show that α-syn aggregates can reach the brain from the gut via the vagal nerve. To understand GI tract contributions to PD, we performed a study that identified the human appendix as a key GI tissue that impacts the risk for PD. This study demonstrated that α-syn aggregates are abundant in the appendix and that removal of the appendix was associated with a reduced risk of PD. It also showed that the appendix contains aberrant truncated forms of α-syn, analogous to those in the PD brain, and that these were more abundant in the appendix of PD patients than in healthy individuals. This innovative work provides the basis for a unique opportunity to understand how the appendix contributes to PD. The proposed study will determine how the appendix, and the α-syn aggregates within, can impact the development of PD. Specifically, this project aims to establish: 1) what gene regulatory changes are prominent in the PD appendix compared to that of healthy controls; 2) the specific truncated forms of α-syn enriched in the PD appendix and their capacity to seed further aggregation; 3) the consequences of initiating α-syn pathology in the appendix on the subsequent development of PD-like pathology in the brain, in vivo. This study will generate detailed genome-wide maps of epigenetic abnormalities in the PD appendix – a resource for understanding gene regulatory and biological pathway changes in the PD GI tract. Profiling the epigenetic mark DNA methylation will be accompanied by an integrative network analysis with transcriptomic data to determine key genes dysregulated in the PD appendix. Next, the identification of the truncated α-syn proteoforms elevated in the PD appendix, will be carried out using top-down mass spectrometry, the gold-standard for intact protein identification. Furthermore, seeding activity for pathogenic α-syn in the appendix of PD cases, will be determined and compared to controls, using powerful biochemical assays. Finally, the capacity for α-syn pathology triggered in the mouse cecal patch – aka the appendix – to lead to the development of PD-like neuropathology in the brain, will be determined. We will also determine if intestinal inflammation in combination with α-syn pathology in the cecal patch augments brain pathology relevant to PD. Together, this study will provide new insights on the mechanisms underlying α-syn abnormalities in the PD gut and its capacity to induce brain neuropathology. Moreover, this work can help shape the development of early PD diagnostics and treatments directed to the accessible GI tract.

帕金森病是一种以运动和非运动为特征的破坏性神经退行性疾病 症状。帕金森病在大脑中的标志性病理是α-突触核蛋白(α-SYN)聚集体的存在， 伴随着黑质多巴胺能神经元的丢失。大脑α-syn病理被认为是 开始于胃肠道(GI)，因为GI功能障碍和GI中存在α-SYN聚集体 肠道症状通常比运动症状早很多年。此外，实验模型表明，α-SYN 集合体可以通过迷走神经从肠道到达大脑。为了了解胃肠道对PD的贡献， 我们进行了一项研究，确定人的阑尾是影响帕金森病风险的关键胃肠道组织。这 研究表明，阑尾内有丰富的α-SYN集合体，切除阑尾 与帕金森病风险降低有关。研究还表明，阑尾含有异常的α-SYN截断形式，类似于帕金森病患者的大脑，而且在帕金森病患者的阑尾中更为丰富 而不是健康的个体。这项创新工作提供了一个独特的机会来了解如何 阑尾有助于帕金森病的发生。 拟议的研究将确定附录和其中的α-SYN聚集如何影响 帕金森病的发展。具体地说，这个项目的目的是确定：1)哪些基因调控变化是显著的 与健康对照组比较；2)富含α-SYN的特定截短形式 PD附录及其播种进一步聚集的能力；3)启动α-SYN的后果 病理在附录中介绍了帕金森病在脑内的后续发展，活体病理。本研究 将在PD附录中生成详细的表观遗传学异常的全基因组地图-这是一个 了解PD GI区的基因调控和生物途径的变化。描述表观遗传学 标记DNA甲基化将伴随着与转录数据相结合的网络分析 确定帕金森病附录中异常表达的关键基因。接下来，对截断的α-SYN进行辨识 在PD附录中升高的蛋白质形式，将使用自上而下的质谱学进行检测，这是完整蛋白质鉴定的金标准。此外，致病α-SYN的播种活性载于 将使用强大的生化分析来确定帕金森病病例，并与对照组进行比较。最后， 在小鼠盲肠补片--也就是阑尾--触发的α-SYN病理能力导致 脑内帕金森病样神经病理的发展将被确定。我们还将确定肠道是否 盲肠补片的炎症与α-SYN病理相结合，增加了与帕金森病相关的脑病理。 总之，这项研究将为帕金森病肠道α-SYN异常的机制提供新的见解 以及它诱导大脑神经病变的能力。此外，这项工作还可以帮助形成早期的 针对可接近的胃肠道的帕金森病诊断和治疗。