In vivo pathway analysis to determine the mechanistic role of susceptibility genes for Parkinson's disease

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Parkinson's disease (PD) is a common and relentlessly progressive brain disease. Its key symptom, slowness of movement, is caused by the death of nerve cells (neurons) that produce a chemical called dopamine in a part of the brain called the substantia nigra. Currently available therapies are inadequate: Firstly, they treat only some, but not all, of the symptoms of the disease. Secondly, they do not modify the underlying disease processes and therefore fail to slow down disease progression. This failure is partially due to our limited knowledge of the mechanisms that cause PD. Over the last 20 years, there has been huge progress with the identification of genes and mechanisms which cause PD that is inherited due to faults (mutations) in genes (familial PD). However, only about 5-10% of PD patients in the UK carry such a familial PD mutation. This project aims to elucidate how inherited factors contribute to the risk of the much more common sporadic form of PD. So-called genome-wide association studies (GWAS) have now identified 24 regions within our genome which contain genes that contribute to the risk of sporadic PD. However, it is not clear how these genes contribute to the risk of PD and, in some cases, which particular gene within such a region is responsible. Our aim is to study those genes which are most likely to contribute to the risk of PD (from hereon called PD GWA genes). We and others believe that these genes will be involved in 3 distinct mechanisms, namely:1) The regulation of energy production and energy maintenance (homeostasis) by cellular components called mitochondria.2) The aggregation and breakdown of proteins by processes called autophagy and cellular components called lysosomes.3) Inflammation (the cellular response to injury and infection). We propose to use zebrafish carrying gene defects which will inactivate these PD GWA genes for our studies. Zebrafish are vertebrates and therefore much more closely related to humans then other lower animal models such as worms or fruit flies. They also offer the opportunity to study the interaction of PD GWA genes with ageing processes. This is important since ageing is the most important risk factor for PD. Zebrafish larvae develop outside the body and are transparent. This makes it relatively easy to study the interaction between neurons and immune cells. Zebrafish are also an excellent animal model for drug discovery. They have already been used for a wide range of other human diseases (including liver, heart and clotting disorders) to elucidate how genes first identified in genome-wide association studies contribute to these disorders. We and others have already been using zebrafish to study familial PD genes. We now want to use our expertise and the major advantages of zebrafish as a model for human diseases to study the PD GWA genes to better understand how they contribute to the risk of sporadic PD. Using a revolutionary new gene editing strategy called 'CRISPR/Cas', we have already made a range of zebrafish lines which carry mutations in 10 of the most important PD GWA risk genes. This pilot work will greatly accelerate the progress of our proposed research. As part of this, we will be studying the effect of these PD GWA risk genes on so-called 'global gene expression'. This involves quantifying how much the brain is using all of the genes in the genome and thereby getting an insight into which biological systems are over or under active. We will also investigate whether PD GWA risk genes interact with familial PD genes. Our work will have a strong focus on the identification of "druggable" targets within these systems. In the future, we are planning to undertake a drug screen against these targets. This will hopefully help us to identify promising drugs which can then be taken into clinical trials for patients with PD.