Development of a novel progressive rat model of Parkinson’s disease
University of Prince Edward Island, University of British Columbia, Laval University, Ottawa Hospital Research Institute, Dalhousie University
The development of effective neuroprotective therapies for Parkinson’s disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. We are developing a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. In previous work, chronic exposure to dietary phytosterol glucosides, as found in cycad seed, has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. The slowly progressive nature of this model, together with its ability to recapitulate various key features of PD, make it ideal for the screening of potential neuroprotective therapies for the treatment of this disease. The goal of this project is to see the BSSG model widely tested, expanded upon, replicated and, thus, verified using a standardized approach. This multi-site validation study will see the model replicated across three different sites, while also providing value-added components based on the unique skill-sets of each institution. At UBC, Dr. Doudet will use PET imaging to monitor degeneration and inflammation over time. At Laval, Dr. Soulet will examine early gastrointestinal changes, an early pre-motor sign of PD. Dr. Schlossmacher will utilize his extensive experience with protein aggregation to do an in-depth assessment of this pathological feature of PD. Finally, Drs. Van Kampen, Tasker and Robertson, at UPEI, will assess late-stage cognitive deficits associated with this model, which may serve a therapeutic screening platform for treatments of PD dementia.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
There is a critical need for neuroprotective therapies for PD. Despite the numerous, seemingly promising, candidates that have arisen over the past decade, nothing has succeeded in the clinic. This may be due, in large part, to the lack of proper tools for screening at the preclinical level. The progressive nature of this model, as well as the recapitulation of multiple features characteristic of PD, will be critical for screening candidates for neuroprotection. The results of this proposal would further validate a model that has the potential to greatly enhance the efficiency of neuroprotectant screening and expedite the discovery of a neuroprotective therapy for PD and possibly treatments for PD dementia.
This study will provide a standardized multi-site validation of the novel progressive BSSG model of PD. In addition to a standardized model replication, UBC will provide longtitudinal assessment of time-dependent changes in markers of degeneration, inflammation and metabolism. Laval will assess time-dependent changes in immune response and early gastrointestinal pathology, now recognized as a key pre-motor indicator of PD. U of Ottawa will provide an in-depth assessment of the regional development of proteinopathy over time. UPEI will examine the appearance and nature of cognitive changes over time, as a potential model of PD dementia. Overall, this study will provide a standardized multi-site validation, while providing value-added components designed to strengthen the utility of this model for screening neuroprotective therapies.