Development of an HTS Assay to Break the Alpha-Synuclein-Glucocerebrosidase Feedback Loop
Rapid Response Innovation Awards, 2012
We aim to develop a novel screening platform to identify candidate drugs to treat Parkinsonís disease.† The screening platform incorporates the link between alpha-synuclein and GBA, the Gaucherís Disease gene. Recent genetic and biochemical data suggest that this link could play a role in the development of Parkinsonís disease. Novel drugs that interfere with this link could thus have show potential as future disease-modifying therapies.
Recent discoveries have highlighted a link between Parkinsonís disease and the gene that can cause Gaucherís Disease, GBA.† It is clear that carriers of the Gaucherís disease variant, who do not develop Gaucherís, have a higher chance of developing Parkinsonís disease. Biochemical data suggests that alpha-synuclein, the protein that accumulates in Lewy bodies in the brain of Parkinsonís patients, affects the function of GBA, and loss of GBA function affects the levels of alpha-synuclein.
The screening platform that we aim to develop would interrogate the presence and localization of these proteins simultaneously, including additional parameters by automated high-throughput microscopy. With such an assay, large libraries of compounds can be screened in the future, to identify starting points for drugs with a new mode of action.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:†††††††††††††††††††††
This project has the potential to provide a platform which many researchers and drug discovery organizations can access and thereby help translate what we know about the alpha-synuclein-GBA link into ideas and molecules that will support the development of future drugs which could halt or slow the progression of Parkinsonís disease.
Our project has the potential to inform us further about the biological significance of the link between alpha-synuclein and glucocerebrosidase in a range of cell systems including PD patientĖderived cells. Furthermore, this study has the potential to impact the work of many researchers and drug discoverers through provision of a quantitative assay system which can been screened for new candidate drugs for PD.
Professor of Clinical Neurology at Institute of Neurology, University College London
Location: London, United Kingdom
Location: Leiden, Netherlands