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

Lead Research Organisation: Imperial College London
Department Name: Life Sciences


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


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Gonzalez-Garcia M (2021) Membrane Interactions and Toxicity by Misfolded Protein Oligomers in Frontiers in Cell and Developmental Biology

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011178/1 30/09/2015 29/09/2023
2131093 Studentship BB/M011178/1 28/09/2018 20/01/2023 Mario Gonzalez Garcia
Description During the first two years of my award and the first few months of the third, I have been able to optimise some laboratory protocols by identifying the ideal conditions to produce potential therapeutic agents for Parkinson's disease. These could bind to oligomeric alpha-synuclein aggregates and inhibit their neurotoxic capacity.

After optimising the synthesis conditions, I was able to identify some initial candidates that seem to bind to alpha-synuclein, based on preliminary data. Currently, I am focussing my efforts in characterising these potential interactions, and in identifying additional therapeutic molecules that could exhibit similar binding properties.

Additionally, as a result of the impact of COVID-19 and the lack of access to research facilities for at least 3 months in 2020, I was able to write a scientific review on toxic interactions of protein oligomers, which has just been accepted and is about to be published.

Updated March 2022: The review I was working on during the first COVID-19 lockdown was successfully published last year (DOI: 10.3389/fcell.2021.642623).

My research during this year has focussed on characterising the binding of potential molecular candidates and the continuation of the synthesis process that gives rise to these binding partners. Negative binding data have been acknowledged and their causes are still being investigated, with the future short-term aim of changing experimental conditions which will lead to the successful generation of binding partners.

In addition, the in vitro effect of one of these molecules that showed preliminary binding ability to alpha-synuclein is being probed in cellular assays involving alpha-synuclein oligomers. This will provide reassurance as to whether the binding partner not only interacts with alpha-synuclein in vitro, but as to whether this actually neutralises the toxicity caused by protein oligomers.
Exploitation Route Hopefully, the identification of therapeutic agents that can directly target the key species at the onset and during development of Parkinson's disease could result in the future direct generation of a novel therapy for this neurodegenerative disease. Should this project not successfully achieve this, it will potentially provide, however, a proof of concept that will certainly be useful for others in the quest for finding therapeutic molecules that inhibit the key toxic abilities of alpha-synuclein aggregates in Parkinson's disease.

In the case of the scientific review, a comprehensive summary of the mechanisms by which protein oligomers involved in several neurodegenerative diseases cause toxicity will provide very useful for the scientific community. It will hopefully serve as a good and clear basis of the main toxicity mechanisms for other research groups, and hence will probably become as a source of inspiratory literature for further research on the field of neurodegeneration.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology