The small SynuClean-D molecule interrupts the formation of the alpha-synuclein amyloid fibres responsible for the onset of Parkinson’s disease, and reverts the neurodegeneration caused by the disease, work led by researchers at the Institute of Biotechnology and Biomedicine (IBB) of the Universitat Autònoma de Barcelona has found.
After analysing over 14,000 molecules, they identified the 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 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 C. 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.
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 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.
The work was supported in part by the y Fundación La Marato de TV3, the Deutschen Forschungsgemeinschaft Center for Nanoscale Microscopy and Molecular Physiology of the Brain, y Ministerio de Economía y Competitividad, Gobierno de Aragón, Instituto de Salud Carlos III, and by the European Research Council.
Jordi Pujols, Samuel Peña-Díaz, Diana F. Lázaro, Francesca Peccati, Francisca Pinheiro, Danilo González, Anita Carija, Susanna Navarro, María Conde-Giménez, Jesús García, Salvador Guardiola, Ernest Giralt, Xavier Salvatella, Javier Sancho, Mariona Sodupe, Tiago Fleming Outeiro, Esther Dalfó, Salvador Ventura
Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons
Proceedings of the National Academy of Sciences Sep 2018, 201804198; DOI: 10.1073/pnas.1804198115
Image: Wellcome Images