Understanding the Molecular Origins of the Toxicity of Alpha-synuclein in Parkinson's Disease

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Parkinson's disease (PD) is a progressive neurodegenerative disorder afflicting 2% of the global population over 65 years of age. It is generally recognised that the hallmark of PD is the deposition of insoluble fibrils of human alpha-synuclein, a pre-synaptic 140-residue protein, in Lewy bodies. There is also significant genetic evidence implicating alpha-synuclein in the pathogenesis of PD, with point mutations (A30P, E46K, H50Q, G51D and A53T) and gene triplication known to cause dominantly inherited early onset PD.The proposal will achieve a conclusive understanding of the structural bases of the toxicity of prefibrilar alpha-synuclein oligomers, which are generally acknowledged to be the most toxic species in the aetiology of PD. This is a top goal that is associated with significant experimental and theoretical challenges owing to the transient nature of these protein states. Indeed, there is currently a poor understanding of the nature of alpha-synuclein oligomers, including the structural and molecular bases of their toxicity.We believe that our research proposal comes at a most opportune time, since we now have all the tools to perform such a study. Our goal is to unveil the molecular bases of the cellular toxicity of alpha-synuclein oligomers by characterising and comparing the structural properties of two types of pre-fibrilar oligomers having similar morphologies but significantly different levels of toxicity (Cremades et al Cell, 2012, 149:1048-59). By using solution and solid-state nuclear magnetic resonance (NMR) spectroscopy in combination with computational biology, we will determine the structural properties of these oligomers and investigate the origins of their selective interaction with biological lipid membranes. Our analysis will be extended to pathological mutants of alpha-synuclein and will be complemented by biophysical and cellular experiments. The aimed interdisciplinary characterisation of the molecular bases of alpha-synuclein oligomers/membrane interactions will have significant impact on the wider academic community studying the molecular bases of amyloid diseases (including Parkinson's, Alzheimer's and Diabetes type II) and wider disciplines such as protein science, biochemistry, NMR spectroscopy, molecular simulations, cellular and molecular biophysics. It is anticipated that the outcomes of this research may directly translate into knowledge leading to new therapeutic approaches in Parkinson's disease and other amyloid-associated disorders.