JAK-STAT immune signalling in PINK1-related Parkinson's disease

帕金森病(PD)是由多巴胺能神经元变性引起的一种破坏性疾病，导致运动和非运动症状。目前还没有治愈或改变疾病的疗法，部分原因是我们仍然缺乏对疾病根本原因的完整了解。虽然临床治疗和病理研究的主要焦点是多巴胺能神经元丢失和相关的运动功能障碍，但包括胃肠道(GI)功能障碍在内的非运动症状正受到越来越多的关注。新的证据表明，异常的肠道炎症可能在帕金森病的发展中起主要作用，肠道屏障的破坏导致全身炎症和神经变性。事实上，病理证据表明，胃肠道的变化可能先于中枢神经系统的变化。其他假设表明，肠道微生物区系的变化可能会引发肠道炎症和胃肠道功能障碍。总之，越来越多的证据支持所谓的肠脑轴是帕金森病和其他几种神经退行性疾病的主要贡献者。因此，使用帕金森病动物模型进行研究对于了解免疫信号通路、肠道炎症、微生物区系和神经变性之间的相互作用是必要的。虽然绝大多数病例是散发性的，但约5%-10%的病例表现出明显的孟德尔遗传，多基因突变已被确定为病例的显性或隐性帕金森病。研究疾病相关突变的后果，如PINK1和PRKN，为揭示帕金森病的致病机制提供了重要线索，并为建立帕金森病的动物模型提供了机会。PD基因的功能研究已经开始涉及到许多机制，主要的假说涉及蛋白质聚集、线粒体功能障碍和自溶体系统的破坏。果蝇已被证明是PINK1/Parkin生物学的领先体内模型，揭示了它们的功能、调节和功能障碍的后果的许多重要见解。在研究保守的免疫信号通路的作用时，我们发现了令人信服的证据，表明JAK-STAT通路在PINK1的发病中起着重要作用。重要的是，JAK-STAT信号在果蝇肠道内稳态中起着至关重要的作用，对生物的健康和寿命有重大影响。本项目将使用先进的组织/细胞特异性遗传操作来剖析线粒体功能障碍在免疫信号激活中的组织水平参与。具体地说，我们将确定哪些组织对PINK1功能的丧失最敏感，以触发JAK-STAT信号，以及哪些细胞发送与哪些细胞接收细胞因子信号。我们将确定局部与系统JAK-STAT信号对生物表型的贡献程度。我们将研究PINK1缺失触发异常JAK-STAT活性的细胞内机制(S)，重点是线粒体功能障碍的特定后果。我们将详细分析PINK1在不同类型的肠道细胞中的细胞自主和非自主需求。我们还将确定PINK1突变和衰老对微生物组的影响，以及微生物组对突变表型的影响。重要的是，我们将评估PINK1-JAK-STAT相互作用在帕金森病小鼠模型中的保守性。这种类型的发现研究将为更清楚地了解疾病原因奠定基础，这对开发更有效的治疗方法至关重要。

Parkinson's disease (PD) is a devastating disease caused by the degeneration of dopaminergic neurons leading to motor and non-motor symptoms. Currently no cure or disease-modifying therapies exist, partly because we still lack a complete understanding of the root-cause of the disease. While a major focus of clinical treatment and pathological investigation are on dopaminergic neuron loss and associated motor dysfunction, non-motor symptoms, including gastrointestinal (GI) dysfunction, are attracting increased attention. Emerging evidence indicates that aberrant intestinal inflammation likely plays a major role in the development of PD, with breakdown of the intestinal barrier leading to systemic inflammation and neurodegeneration. In fact, pathological evidence indicates that changes in the GI tract may precede alterations in the central nervous system. Additional hypotheses suggest that changes in the intestinal microbiota may trigger gut inflammation and GI dysfunction. Altogether, a growing body of evidence supports the so-called gut-brain axis as a major contributor to PD as well as several other neurodegenerative conditions. Thus, research using animal models of PD is necessary to understand the interplay between immune signalling pathways, intestinal inflammation, microbiota and neurodegeneration. While the vast majority of cases are sporadic, about 5-10% of cases show a clear Mendelian inheritance, and multiple gene mutations have been identified to case dominant or recessive PD. Studying the consequences of disease-linked mutations, such as with PINK1 and PRKN, gives important clues into the pathogenic mechanisms across the spectrum of PD, and provides the opportunity to develop animal models of PD. Functional studies of PD genes have begun to implicate a number of mechanisms with leading hypotheses implicating a central role for protein aggregation, mitochondrial dysfunction, and disruption to autolysosomal systems. Drosophila have proven to be a leading in vivo model of PINK1/Parkin biology, revealing many important insights into their function, regulation and the consequences of their dysfunction. Investigating the role of conserved immune signalling pathways, we have found compelling evidence that the JAK-STAT pathway significantly contributes to Pink1 pathogenesis. Importantly, JAK-STAT signalling is known to play a crucial role in gut homeostasis in Drosophila, having a major impact on organismal health and lifespan.This project will use advanced tissue/cell-specific genetic manipulations to dissect the tissue-level involvement of mitochondrial dysfunction in immune signalling activation. Specifically, we will determine which tissues are most sensitive to loss of Pink1 function to trigger JAK-STAT signalling, and which cells send versus which cells receive the cytokine signals. We will determine the extent to which local versus systemic JAK-STAT signalling contributes to the organismal phenotypes. We will investigate the intracellular mechanism(s) by which loss of Pink1 triggers aberrant JAK-STAT activity, focussing on specific consequences of mitochondrial dysfunction. We will provide a detailed analysis of cell-autonomous and non-autonomous requirement of Pink1 in the various intestinal cell types. We will also determine the impact of Pink1 mutation and ageing on the microbiome and the impact of the microbiome on the mutant phenotypes. Importantly, in parallel we will assess the conservation of the PINK1-JAK-STAT interaction in a murine model of PD. This type of discovery research will lay the foundations for a clearer understanding of the disease cause, which is essential to develop more effective therapies.