Dissecting molecular mechanisms of Parkinson's disease

Parkinson's disease is devastating neurodegenerative disorder, that remains incurable due to our lack of understanding about its cause at a molecular level. Understanding the molecular origins of human diseases requires accurate characterisation of the underlying processes. However, PD is complex and multifactorial, and it is therefore challenging to choose which molecular events to study, and indeed which molecular events are causative. Notably, 90% of Parkinson's disease cases are sporadic, whilst 5-10% are familial due to an identified mutation. Autosomal dominant and autosomal recessive forms of PD share many common pathological and clinical features with the sporadic PD, albeit with some variation. Importantly in this group of familial PD, the causative gene and protein is known and therefore provides a robust starting point for understanding potential molecular causative events in PD. Taken further, the large genome wide association studies in PD have highlighted that genetic risk to sporadic PD is caused by aberration in pathways that broadly map to those raised by the mendelian forms of PD: namely the abnormal aggregation of proteins, abnormal function of mitochondria, abnormal clearance mechanisms by lysosomes, and inflammation. Thus, the outcomes from both mendelian genetics and common variation converge, and therefore may be used to rationalise the basis for determining causation in both familial and sporadic PD. I propose a framework within which selected human familial forms of PD (mitochondrial-PD, lysosomal-PD, and proteinopathy-PD) are used to in first to understand key molecular causative events at the onset of disease. Informed by the human genetics, this will focus first, in theme 1, on specific pathways to disease, in particular, how and why protein aggregation occurs inside cells, and then how the aggregation affects cellular function, and organellar function with mitochondria and lysosomes. In order to achieve this aim, we will apply sophisticated methods derived from physical chemistry and biophysics that allow us to visualize each protein aggregate as it is formed, and therefore understand the size and structure of the aggregates at unprecedented resolution. The application of novel biophysical methodology to track the intracellular aggregation process of alpha-synuclein in iPSC derived models of PD should reveal the structure of the toxic species of alpha-synuclein, and determine how it interacts with, and disrupts specific cellular processes such as mitochondrial function. In theme 2, we ask whether different cell types in the human brain play an important role in Parkinson's disease pathogenesis. Glial cells play crucial roles in neuronal function, and alterations in glial cells are known to occur in PD and induce inflammation in the brain. Utilising iPSC derived neurons and astrocytes, we will investigate how glial cells may be activated during PD, and how alterations in astrocyte function affect neurons. In theme 3, we will utilize the information from the mendelian forms of PD to generate a framework of data. This framework will then be used to interrogate the mechanisms that underlie a large group of cells derived from patients with sporadic PD. Specifically it will reveal whether the sporadic PD population is heterogeneous in its molecular aetiology, whether the genetic and molecular drivers of any individual with PD clusters closely to the mendelian forms. As a consequence, it will ultimately determine whether patients with sporadic disease can be subdivided according to their molecular causes. If the sporadic PD population in composed of forms of PD that are 'mitochondrial' or 'lysosomal' for example, then this would raise the possibility that therapies in fact need to be designed to address the molecular basis of an individual's form of PD, in this way laying the foundation for developing personalised medicine approaches in PD.