Protection of neurons in vitro and in vivo from Synuclein toxicity by molecular tweezers

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Parkinson's disease is an age-related neurodegenerative disorder in which aggregated clumps of a protein termed alpha-synuclein form in neurons, the cells in the brain which relay electrical information. These clumps are the defining key hallmark pathology of Parkinson's and are called Lewy bodies (LB). In a related disease, multiple system atrophy (MSA), the protein clumps form in the support cells, called glia. The diseases are therefore related and may benefit from a therapy to prevent the formation and spread of alpha-synuclein protein clumps. The development of therapeutic strategies to prevent the formation and spread of alpha-synuclein protein clumps and prevent cell death in Parkinson's and MSA has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence demonstrates the importance of the alpha-synuclein clumps in disease pathology and has led to consider the therapeutic potential of several strategies aimed at reducing the burden and toxicity of alpha-synuclein accumulation. Our objective here is to build upon the unique experimental models of disease and complementary expertise of the Consortium. Members of the research team specialise in working in brain cells from mice, and with human neurons derived from stem cells made from Parkinson's patients. Others members of the team work on animal models of Parkinson's and MSA which model how alpha-synuclein may spread in the brain. We will use these models in laboratories in France and in the UK to test a novel molecular therapy called "molecular tweezer" drug which has been shown to inhibit aggregation and toxicity of other similar proteins which clump in other diseases. The drug may therefore protect neurons grown in the laboratory and neurons in the brain from Parkinson's or MSA-associated cell death. By probing the mechanisms and application of "molecular tweezers" to Parkinson's and MSA the project will demonstrate the use or not of such a therapy to prevent alpha-synuclein-mediated cell death.