The contribution of the vermiform appendix to Parkinson's disease

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 症状脑中PD的标志性病理学是α-突触核蛋白（α-syn）聚集体的存在， 沿着黑质多巴胺能神经元的丧失。大脑α-syn病理学被认为是 从胃肠道（GI）开始，因为GI功能障碍和GI中存在α-syn聚集体 尿道通常先于运动症状多年。此外，实验模型表明，α-syn 聚集物可以从肠道经由迷走神经到达大脑。为了了解胃肠道对PD的影响， 我们进行了一项研究，将人类阑尾确定为影响PD风险的关键GI组织。这 研究表明，阑尾中有大量的α-syn聚集体， 与PD风险降低相关。它还表明，阑尾含有异常截断形式的α-syn，类似于PD大脑中的α-syn，并且这些在PD患者的阑尾中更丰富 比健康的人。这项创新工作提供了一个独特的机会，了解如何 阑尾也会导致腹膜透析。 这项拟议中的研究将确定阑尾和其中的α-syn聚集体如何影响 发展PD。具体而言，本项目旨在建立：1）哪些基因调控变化是突出的 与健康对照相比，PD附录中的α-syn; 2）在PD附录中富集的α-syn的特定截短形式 PD附录及其种子进一步聚集的能力; 3）启动α-syn的后果 附录中的病理学对随后体内脑中PD样病理学的发展的影响。本研究 将在PD附录中生成详细的表观遗传异常的全基因组图谱-这是一个资源， 了解PD胃肠道的基因调控和生物学途径变化。分析表观遗传 标记DNA甲基化将伴随着转录组数据的综合网络分析， 确定PD阑尾中失调的关键基因。接下来，确定截断的α-syn 将使用自上而下的质谱法（完整蛋白质鉴定的金标准）进行PD附录中升高的蛋白质形式。此外，致病性α-syn在附录中的接种活性 将使用强大的生物化学测定来确定PD病例并与对照进行比较。最后 在小鼠盲肠斑（又名阑尾）中触发α-syn病理的能力， 将确定脑中PD样神经病理学的发展。我们还将确定肠道 盲肠补片中的炎症与α-syn病理学的组合增强了与PD相关的脑病理学。 总之，这项研究将为PD肠道中α-syn异常的潜在机制提供新的见解 以及其诱发脑神经病理学的能力。此外，这项工作可以帮助塑造早期发展， 针对可触及胃肠道的PD诊断和治疗。

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.