Molecular signatures of Parkinsons disease in the gut and brain

项目摘要 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 可能起源于胃肠道(GI)的症状和特定病理。大脑中的帕金森病病理 涉及α-突触核蛋白的神经毒性聚集和黑质中多巴胺能神经元的丧失。 在胃肠道，甚至在运动症状出现前几年，也发现了类似的α-突触核蛋白病理。 也有证据表明，α-突触核蛋白聚集体通过迷走神经从肠道到达大脑，并且 帕金森病脑的病理分期支持胃肠道起源。因此，致病的α-突触核蛋白来源于 胃肠道被认为通过迷走神经逆行运输扩散到大脑，从而导致黑质神经变性和帕金森病。 然而，是什么促进了α-突触核蛋白在肠道中的积聚和扩散，目前仍不清楚。 在这项研究中，我们问：在PD患者的胃肠道中，哪些分子特征使疾病的传播成为可能 阿尔法-突触核蛋白对大脑的病理？我们最近发现，α-突触核蛋白的病理在 正常人和帕金森病患者的人体蠕虫状阑尾。我们的研究表明：(I)附录是 致病形式α-突触核蛋白的储存库和(Ii)切除阑尾大大减少了 发展为帕金森病的风险。重要的是，这项工作表明，帕金森病患者和健康人的能力一定不同 来管理α-突触核蛋白的病理学。我们假设帕金森病和健康人之间的关键区别是 阑尾由自噬-溶酶体途径控制，而自噬-溶酶体途径是调节阑尾降解的关键途径。 以及致病的α-突触核蛋白的传播。 DNA甲基化等表观遗传标记有效地调节自噬-溶酶体中基因的活性 途径，并参与自噬随着年龄的下降。我们的数据显示，在帕金森氏症大脑的神经元中，DNA 甲基化异常确实发生在自噬-溶酶体基因及其转录 监管失调。在这项研究中，我们现在将确定自噬时DNA甲基化异常- 溶酶体基因存在于帕金森病患者的阑尾。我们将在自噬-溶酶体中定位DNA甲基化 基因(n=665)，并对帕金森病附录进行转录转录研究。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帕金森病的阑尾和大脑中。接下来，我们 将确定自噬-溶酶体基因在阑尾的年龄依赖性调节，以及PD是否 患者在这些基因上表现出老化的表观遗传和转录模式的变化。共同努力，我们的研究将 为帕金森病肠道和病理中α-突触核蛋白异常的机制提供新的见解 大脑的进展。这项工作将对帕金森病的早期诊断和治疗的发展起到促进作用 指向可到达的胃肠道。

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.