Study Rationale:
Multiple lines of evidence indicate that alpha-synuclein forms aggregates similar to those adopted by infectious prion proteins, and that these toxic clusters are responsible for the degeneration of dopamine-producing neurons Parkinson’s disease (PD). In this study, we aim to identify prion-busting compounds that can clear toxic alpha-synuclein aggregates from the brain — molecules that could be developed into a disease-modifying or even curative treatment for PD. The most efficient of these compounds will then be further developed into an orally available pill or capsule for the treatment of PD. A similar approach has already resulted in a drug for the treatment of Alzheimer’s disease that has been shown to be safe when administered to humans.
Hypothesis:
Anti-prion compounds that stabilize alpha-synuclein molecules in a form incapable of aggregation can also be used to destroy pre-existing toxic alpha-synuclein clusters. This elimination should rescue remaining neurons, providing a disease-modifying or even curative treatment of Parkinson’s.
Study Design:
This project is based on lead compounds that have already demonstrated promising, prion-busting characteristics. Several approaches will be used to optimize their ability to efficiently eliminate toxic alpha-synuclein aggregates and protect neurons. In addition, the most promising compounds will be compared to each other in terms of their ability to enter neurons in the brain and to disassemble and destroy any alpha-synuclein aggregates found there. Finally, the compounds´ therapeutic potential will be assessed in a pre-clinical model for PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The destruction of toxic alpha-synuclein aggregates is the most favored approach to the treatment of Parkinson’s disease. Identification of an anti-prion drug candidate with the described features will allow for validation of this strategy by demonstrating its efficacy in neuronal cells and pre-clinical models and represents an important step in pharmaceutical development.
Next Steps for Development:
Once the anti-prion compound is shown to be effective in pre-clinical models, it has the potential to be developed into a disease-modifying treatment that can halt Parkinson’s by removing the disease-causing toxic alpha-synuclein aggregates. The most promising compounds from the project will be further tested for their safety and efficacy in human studies.