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

PINK1 相关帕金森病中的 JAK-STAT 免疫信号传导

• 批准号: MR/X008142/1
• 负责人: Alexander Whitworth
• 金额: $ 51.28万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX008142%2F1
• 关键词: JAK; STAT; immune; signalling; PINK1

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.

帕金森病（Parkinson's disease，PD）是一种由多巴胺能神经元变性引起的破坏性疾病，其导致运动和非运动症状。目前还没有治愈或改善疾病的疗法，部分原因是我们仍然缺乏对疾病根源的全面了解。虽然临床治疗和病理学研究的主要焦点是多巴胺能神经元损失和相关的运动功能障碍，但非运动症状，包括胃肠道（GI）功能障碍，正吸引越来越多的关注。新出现的证据表明，异常的肠道炎症可能在PD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，病理学证据表明，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，肠道微生物群的变化可能引发肠道炎症和GI功能障碍。总之，越来越多的证据支持所谓的肠-脑轴是PD以及其他几种神经退行性疾病的主要贡献者。因此，使用PD动物模型的研究对于了解免疫信号通路、肠道炎症、微生物群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%的病例显示出明显的孟德尔遗传，并且已鉴定出多个基因突变可导致显性或隐性PD。研究疾病相关突变的后果，如PINK 1和PRKN，为PD的致病机制提供了重要线索，并为开发PD动物模型提供了机会。PD基因的功能研究已经开始涉及许多机制，其中主要假设涉及蛋白质聚集、线粒体功能障碍和自体溶酶体系统破坏的核心作用。果蝇已被证明是PINK 1/Parkin生物学的领先体内模型，揭示了许多关于其功能，调节及其功能障碍后果的重要见解。研究保守的免疫信号通路的作用，我们发现了令人信服的证据，JAK-STAT通路显着有助于Pink 1发病机制。重要的是，JAK-STAT信号传导在果蝇的肠道稳态中起着至关重要的作用，对生物体的健康和寿命有着重要的影响。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传导激活中的组织水平参与。具体来说，我们将确定哪些组织对Pink 1功能的丧失最敏感，以触发JAK-STAT信号，以及哪些细胞发送细胞因子信号，哪些细胞接收细胞因子信号。我们将确定局部与系统JAK-STAT信号传导对生物体表型的贡献程度。我们将研究Pink 1缺失触发异常JAK-STAT活性的细胞内机制，重点关注线粒体功能障碍的特定后果。我们将提供一个详细的分析细胞自主和非自主的需求Pink 1在各种肠道细胞类型。我们还将确定Pink 1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，我们将同时评估PD鼠模型中PINK 1-JAK-STAT相互作用的保守性。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，这对于开发更有效的疗法至关重要。