The aggregation/fibrillation of the presynaptic protein alpha-synuclein is a key factor in the development of Parkinson’s disease. There is a critical need for an effective treatment of Parkinson’s disease, since current therapies, while effective early on, typically lead to dose-limiting side-effects with time, and there is no known way to stop or halt progression of the disease.
We have recently discovered that certain polyphenols have the potential to inhibit fibrillation of alpha-synuclein and disaggregate existing fibrils in vitro. The aim of this proposal is to follow up on these observations by determining whether these compounds are effective in vivo at preventing neurodegeneration that is induced by abnormal alpha-synuclein aggregation.
These experiments will use two different rodent model systems of PD (rats and mice that overexpress human alpha-synuclein and show pathological changes similar to those seen in PD). If successful, these studies will lay the groundwork for future human trials aimed at slowing or halting the progression of Parkinson’s disease.
The importance of the proposed work lies in its potential to lead to therapeutic approaches to prevent further progression of the disease. This will be the first study to validate the target of synuclein aggregation as a preventable neurodegenerative phenomenon in rodents, and could provide the first evidence that polyphenols (or any compounds) can prevent alpha-synuclein aggregation and neurodegeneration in vivo using rodent models of PD.