Objective/Rationale:
The lack of a pre-clinical model that exhibits key features of human Parkinson’s disease is an impediment to research progress. In this project we will determine whether a novel genetically altered pre-clinical model, called the ‘xenomitochondrial’ pre-clinical model , has key features of Parkinson’s disease lacking in other pre-clinical models. The pre-clinical model has relatively mild defects in a key mitochondrial pathway for energy generation. If we find key features of Parkinson’s disease evolve with aging of this pre-clinical, it will open new research doors into therapy development.
Project Description:
We will investigate the brain regions involved in Parkinson’s disease in the pre-clinical model, looking for evidence that only those regions affected in Parkinson’s disease are also affected in the pre-clinical model. This will be achieved by microscopically determining the numbers of brain cells in key brain areas in pre-clinical models of 3, 12 and 24 months of age (representing human ages of approximately 10, 35 and 70 years old). At the same age points, we will also determine whether the movement impairments seen in Parkinson’s disease patients evolve in the pre-clinical. We can achieve this in a one year grant as we have established aging pre-clinical model groups.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The pre-clinical model under investigation in the project is unique in having an altered mitochondrial genome. This small genome, inherited from our mothers, codes for a few important proteins involved in a biochemical pathway for cellular energy generation. This pathway has long been implicated in Parkinson’s disease progression. If we are successful in showing key features of Parkinson’s disease with aging in this pre-clinical model, it will open new avenues to discover markers of early Parkinson’s disease for earlier diagnosis, and new treatment strategies based on improving the energy-generating defects.
Anticipated Outcome:
We expect to learn from this project whether our novel pre-clinical model holds promise as a powerful new research tool for Parkinson’s disease. Our preliminary data to date suggests certain features of Parkinson’s disease exist in the pre-clinical model. The successful execution of the research plan will tell us if the pre-clinical model has sufficient Parkinson’s disease features to qualify it as a bone fide Parkinson’s disease model. If so, the Parkinson’s disease research community will have available a new model for both tracing the development of the disease in brain cells, and to explore new treatment approaches.
Final Outcome
The aim of the study was to characterize age-related brain pathology and behavioral measures to understand whether a unique genetically modified model created by Dr. Trounce and Dr Carl Pinkert, may be an improvement on current PD models. The model is engineered to have a defective mitochondrial energy generating capacity. This one-year grant has been successfully completed. Our data suggest the model develops a pre-clinical PD syndrome by 24 months of age. It has a compelling suite of age-related features that may model PD better than other models produced around the world. We will certainly be extending this study, for example to find relevant stressors that may accelerate the pathology so that a valuable new pre-clinical model for drug testing can be validated for use by the PD research community.