Biomolecular design to target neurotoxic protein oligomers in Parkinson's disease

The aberrant aggregation of the alpha-synuclein (aSyn) protein has been strongly linked to the neuronal impairment that is characteristic of a set of debilitating neurodegenerative diseases collectively known as synucleinopathies, of which Parkinson's diseases is the most prevalent one. The oligomeric species populated during the aggregation of aSyn have been identified as the crucial pathological agents that cause neurotoxicity, mainly through the disruption of the membrane integrity, which leads to downstream generation of reactive oxygen species and mitochondrial dysfunction. Previous research from the host lab characterised the structural features of the toxic oligomeric species involved in the molecular mechanisms responsible for the neurotoxicity observed in Parkinson's disease.

Currently, therapies available for Parkinson's disease function by only ameliorating the symptoms but do not halt the progression of the disease. It is therefore necessary to seek alternative therapeutic routes that directly target the molecular mechanisms of the disease. Immunotherapy, for example, has been recently identified as an encouraging approach that disrupts aSyn aggregation. However, clinical trials involving antibodies have been unsuccessful, as a result of their inability to access the intracellular aggregate targets, as well as because of their significant immunogenic profile.
We propose to use the structural knowledge of oligomeric aSyn aggregates, as well as the understanding of the mechanism generating their toxic action to identify new therapeutic agents that can directly target the key species at the onset and development of Parkinson's disease. We will use an approach based on in vitro and in vivo investigations to assess and optimise the ability of these molecules in suppressing the toxicity of aSyn aggregates