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

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.

Aberrant activation of immune signalling in the gut has emerged as a leading unifying hypothesis in the pathogenic mechanism(s) of Parkinson's disease (PD). Intestinal inflammation and alterations in the gut microbiota are proposed to contribute to initiation and progression of pathology in PD (the gut-brain axis).

The PD genes, PINK1 and PRKN, function to maintain mitochondrial homeostasis via mitophagy. However, how loss of PINK1 or Parkin affects gut physiology or systemic inflammation is poorly understood. Using Drosophila, a preeminent in vivo model for PINK1/Parkin biology, to investigate 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 genetic approaches 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.