Dr A De Simone
Imperial College London
Understanding the Molecular Origins of the Toxicity of Alpha-synuclein in Parkinson's Disease
Parkinson's disease & PD-related disorders|Alzheimer's disease & other dementias
In this project we assembled a cohort of complementary skills and combined our longterm research programmes to carry out an interdisciplinary study of the structural bases of the toxicity of prefibrilar alpha-synuclein oligomers in view of the crucial interaction with the membrane, which represents the key step in the aetiology of Parkinson’s disease. Our research proposal comes at a most opportune time, since we now have all the tools, background research and materials to perform such an ambitious study. The proposal is articulated on three independent and complementary streams of increasing scale of complexity (i.e. from oligomers structure to membrane interaction and to the effects of pathological mutations). To fulfil this ambitious goal, we will carry out an investigation of solid-state NMR (ssNMR), solution NMR and computational biology that will provide an accurate structural characterisation of toxic and non-toxic oligomers, previously individuated by a part of the team (Cremades et al, Cell, 2012 149:1048-59). Moreover, to probe the selective interaction of the two types of oligomers with a variety of lipid membranes, we will adapt our recent approach that successfully unveiled the nature of the interaction between monomeric alpha-synuclein and lipid membranes (Fusco et al, Nature Communications, 2014 5:3827). The structural investigation will be complemented biophysical and cellular toxicity measurements to define the underlying structural bases of cellular toxicity of alpha-synuclein.