Mitochondrial proteins as novel therapeutic targets in Parkinson's disease

Background
Understanding the critical cellular and molecular events that underlie the development of a patient's symptoms remains a crucial challenge for Parkinson's disease (PD) research. The identification of key proteins and pathways that mediate neurodegeneration offers the best possible chance of developing disease-modifying therapies. There is already a strong body of evidence demonstrating that synapses are a major pathological target in PD and related conditions (e.g. Alzheimer's disease and motor neuron disease) (Wishart et al., 2012; Gillingwater & Wishart, 2013). Alterations in synaptic structure and function have been repeatedly found to precede neuronal cell death in the course of disease. Thus, identifying the molecular pathways that underlie synaptic pathology in PD and related conditions offers the opportunity to better understand these devastating diseases and develop novel, effective therapies. One major regulator of synaptic pathology in PD is alpha-synuclein. Mutations in the gene encoding this synaptic protein result in familial forms of the disease. However, we don't fully understand how alpha-synuclein controls synaptic stability and function (Lashuel et al., 2013). Here, we will build on novel preliminary data generated by collaborative experiments from the host laboratories showing that alpha-synuclein mediates synaptic stability by regulating synaptic mitochondria. Our pilot experiments have identified 37 novel mitochondrial proteins whose levels are regulated by alpha-synuclein, with preliminary pre-clinical data demonstrating that several of these mitochondrial proteins are capable of directly regulating synaptic stability in vivo. This project will build on these findings in order to establish key mitochondrial proteins and pathways that modulate synaptic degeneration and disease pathogenesis in PD, leading ultimately to targeted therapies capable of protecting synapses and modifying disease.

Aims
The current proposal addresses the hypothesis that "targeting of alpha-synuclein-dependent mitochondrial proteins modulates synaptic degeneration in PD". The student will address this hypothesis after receiving training in a range of inter-disciplinary techniques and approaches offered by the host laboratories. The Gillingwater laboratory will use their expertise in molecular neuropathology, neurodegenerative disease modelling and pre-clinical therapy testing to explore the impact of targeting alpha-synuclein-dependent mitochondrial proteins on synaptic stability and function in vivo. The Wishart laboratory will use their expertise in performing state-of-the-art proteomic screens (with subsequent bioinformatics analyses) and establishing genetic screens in Drosophila to identify molecular mechanisms through which alpha-synuclein-dependent mitochondrial proteins modulate synaptic stability in PD. The Tokatlidis laboratory will use their background in characterising mitochondrial biogenesis in health and disease (Kallergi et al., 2014) to establish the functional characteristics of our identified mitochondrial proteins, using an established in vitro (yeast) model system. Thus, using a combination of in vitro and in vivo model systems, alongside state-of-the-art cellular, biochemical and molecular techniques, we will undertake a thorough characterisation of alpha-synuclein-dependent mitochondrial proteins, establish their role in synaptic mitochondria, and determine the extent to which manipulating their expression can modulate PD-associated pathology.