Understanding the genes for Parkinson's disease

We now know many of the genes which cause and predispose to Parkinson's disease but for many others, we only know their chromosomal position. In this grant we seek to find these genes and work out how the function of all the genes for the disease relate to each other. We already know that many of the genes for the disease are involved in two related processes: autophagy (how the cell removes damages cell components and proteins) and mitophagy (how the cell removes damaged mitochondria). We will assess whether these new genes are in the same pathways or if there are other relevant pathways involved in the disease Finally, we will develop cellular assays for these pathways so that we can work towards developing drugs which correct the defects we have identified.

Parkinson's disease is the most common neurodegenerative movement disorder, affecting in access of 120,000 individuals in the United Kingdom, and is uniformly fatal with no disease course modifying therapy available. Genome wide association (GWA) studies have been outstandingly successful in identifying regions of the human genome that are associated with increased risk for a wide range of common human disorders. This is true for Parkinson's disease, where in excess of twenty risk loci have been identified. The major challenge for both academic and industrial researchers is to translate the identification of these genomic regions into biological insights into the molecular aetiology of Parkinson's, which in to turn can inform drug development efforts in this area. To achieve this, the causative variants responsible for the WG association - in most cases likely to be alterations in specific genes - need to be identified and characterized. In this proposal we will use gene expression and splicing analysis to assess the functional role of genes implicated by PD GWA studies, combined with cellular and in vivo studies, to take the key next steps required for evaluation of the role of implicated genes in the molecular pathogenesis of PD and their status as putative drug targets.

The genetic and functional characterization of genetic loci implicated in the pathogenesis of idiopathic Parkinson's disease by genome wide association studies will have important implications and impact outside of an immediate academic audience.
With more than 120,000 people in the UK currently with Parkinson's, there is an urgent health and economic demand for new treatments. The impact of Parkinson's disease will increase over the coming decades as the UK population ages, emphasising the urgency of developing therapies for this disorder.
We will start by precisely identifying the genes for the disorder and their genetic mechanism through gene expression analysis in parallel with our work outside this proposal in which we are carrying out sequence analysis of PD cases. This genetic, gene expression and bioinformatic work will tell PD researchers including in the pharma industry the biochemical players in the pathways to disease and tell us whether, for each of the genes, we should consider gain or loss or change of function as the pathogenic mechanism.
From our and others previous work, we already know three pathways which are involved in the disorder: autophagy, mitophagy and endosomal pathways. We will continue to explore the role of the known PD genes and mutations on these pathways and seek to identify other molecular components of these pathways. This process will both be guided by the genetic analysis above and equally will guide the genetics as interactors identified in this work may be novel PD loci.
As we develop a deeper cellular understanding of the pathogenic biochemical networks we will develop assays which we will convert to medium throughput assays to enable screening for the compounds which perturb these networks. This information will feed into drug development programs in the academic and pharmaceutical sector, providing a bridge over the gap between the basic genetic insights into PD and translational efforts to produce novel therapies.
The development of disease modifying therapies based upon data generated by this study will have major ramifications for the pharmaceutical sector, the National Health Service and, most importantly, individuals with Parkinson's or at risk of developing the disease. While it is difficult to quantify the impact of a disorder such as Parkinson's on the nation, a recent study (Findley LJ, Parkinsonism and Related Disorders 13: S8-S12, 2007) provides an estimate of between £449 million and £3.3 billion to the UK economy. DiLuca and Olesen (Neuron 82: 1205-1208) estimate the cost of Parkinson's to the European economy as being close to £10 billion (with £5 billion being in direct health care costs), and so it is clear that a disease modifying therapy slowing the disease course or delaying the age of onset would have a major impact on the health and wealth of the United Kingdom. The major challenge for the pharmaceutical industry in the field of neurodegeneration with regarding to developing such a therapy has been to identify clear drug targets, a contrast with the field of cancer biology where a genetic approach has yielded a number of tractable targets. In PD, the number of clear disease modifying drug targets has been limited to a handful, including three (SNCA, LRRK2, and GBA) that have had their status reinforced by their identification by GWA studies for PD. To proceed from a list of circa 20 disease associated loci to a tractable and rationally stratified list of potential drug targets, a critical and required step is the thorough characterization of these loci. This proposal provides a structured and detailed series of work packages to directly address this need.