Molecular signatures of Parkinsons disease in the gut and brain

项目摘要 帕金森病（PD）是一种以运动和非运动为特征的毁灭性神经退行性疾病 症状和可能起源于胃肠道（GI）的特定病理。脑PD病理学 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损失。 在胃肠道中，甚至在运动症状发作前数年就已检测到类似的α-突触核蛋白病理学。 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， PD脑的病理分期支持GI起源。因此，来源于细胞的致病性α-突触核蛋白 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PD。 然而，是什么促进了α-突触核蛋白病理在肠道中的积累和传播仍然是未知的。 在这项研究中，我们问：PD患者胃肠道中的分子特征是什么，使得 阿尔法突触核蛋白的病理变化吗我们最近发现，α-突触核蛋白的病理是普遍的， 人阑尾在健康和PD个体。我们的研究表明，（i）阑尾是 α-突触核蛋白的致病形式的储存库和（ii）阑尾的切除大大减少了 发生PD的风险。重要的是，这项工作表明，PD和健康个体必须在他们的能力不同， 来控制α-突触核蛋白的病理我们假设帕金森病和健康人之间的一个关键区别 阑尾是在控制自噬-溶酶体途径-一个关键途径，介导的降解 以及致病性突触核蛋白的扩散 表观遗传标记如DNA甲基化有效地调节自噬-溶酶体中基因的活性， 自噬通路，并参与自噬随年龄的下降。我们的数据显示，在PD大脑的神经元中， 甲基化异常确实发生在自噬-溶酶体基因，沿着它们的转录 失调在这项研究中，我们现在将确定自噬过程中的DNA甲基化异常- 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 基因（n=665），并进行转录组学研究的PD附录。我们还将确定DNA 自噬-溶酶体基因的甲基化扰动反映在PD阑尾和脑中。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转录模式。我们的研究将 为PD肠道和病理组织中α-突触核蛋白异常的潜在机制提供了新的见解。 在大脑中的进展。这项工作将形成早期PD诊断和治疗的发展 直接进入胃肠道

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.