Is the Xenomitochondrial Mouse an Ideal PD Model

Rapid Response Innovation Awards 2012
Joint Funded by Shake It Up Australia Foundation and The Michael J. Fox Foundation for Parkinson’s Research

The lack of a pre-clinical model that exhibits key features of human Parkinson’s disease (PD) 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 PD 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 PD 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 PD in the model, looking for evidence that only those regions affected in PD 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 PD 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 PD disease progression. If we are successful in showing key features of PD with aging in this pre-clinical model, it will open new avenues to discover markers of early PD 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 PD. Our preliminary data to date suggests certain features of PD exist in the pre-clinical model. The successful execution of the research plan will tell us if the pre-clinical model has sufficient PD features to qualify it as a bone fide PD model. If so, the PD 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.

Ian Andrew Trounce, PhD
Center for Eye Research Australia

Zane Andrews, PhD
Neuronal Metabolism and Degeneration Lab

David Moses MD, FRACP
Department of Clinical Neuroscience and Neurological Research