Parkinson's disease is the second most common incurable neurodegenerative disorder after Alzheimer's disease. It is characterised by the accumulation of protein deposits in dopaminergic neurons (in charge of producing dopamine) in the form of amyloid fibres. These aggregates are formed mainly by the alpha-synuclein protein and in a very complex manner, which makes it complicated to identify molecules which could prevent or revert the process and the neurodegeneration associated with it.
A scientific collaboration led by researchers at the Institute of Biotechnology and Biomedicine (IBB) of the Universitat Autònoma de Barcelona has identified a molecule which halts and reverts this neurodegeneration. After analysing over 14,000 molecules, they found the SynuClean-D molecule, which inhibits the aggregation of the alpha-synuclein protein and breaks the already formed amyloid fibres, thus preventing the initiation of the process causing the onset of the neurodegenerative Parkinson's disease.
Through experiments conducted with the small Caenorhabditis elegans worm, one of the most commonly used animal models in neurodegenerative diseases, researchers were able to verify that by administering it through food, the molecule was capable of notably reducing alpha-synuclein aggregations, preventing the spread of toxic aggregates and therefore avoiding the degeneration of dopaminergic neurons.
"Everything seems to indicate that the molecule we identified, the SynuClean-D, may provide therapeutic applications for the treatment of neurodegenerative disases such as Parkinson's in the future", UAB researcher and coordinator of the study Salvador Ventura points out.
To identify SynuClean-D researchers developed a methodology capable of indentifying the alpha-synuclein aggregation inhibitors among thousands of molecules. Once identified, an in vitro biophysical characterisation was conducted of their inhibiting activity and tests were run to discover their behaviour with human neural cell cultures, before testing it in animal models of the disease (the Caenorhabditis elegans worm). These animals express the alpha-synuclein in the muscle or in dopaminergic neurons. The experiments demonstrated that the administration of the identified inhibitor reduced protein aggregation, improving the mobility of the animal and protecting it from neural degeneration.
Participating in the study were researchers from the IBB-UAB and the UAB Department of Biochemistry and Molecular Biology Salvador Ventura, Jordi Pujols and Samuel Peña (lead authors of the article), Francisca Pinheiro, Anita Carija and Susana Navarro; researchers from the UAB Department of Chemistry Danilo González and Mariona Sodupe (ICREA researcher); and UAB Institute of Neuroscience researcher Esther Dalfó. Also collaborating in the study were researchers from the Barcelona Institute for Biomedical Research, the University of Barcelona, the University of Vic, the University of Zaragoza, the University Medical Center Göttingen, Germany; the Sorbonne University, France; the Max Planck Institute for Experimental Medicine, Germany; and Newcastle University, UK. The research was funded by the TV3 Marathon.
Proceedings of the National Academy of Sciences