Theme 3: Novel animal models of early cell and circuit dysfunction in Parkinson's

Research Banner Sarah

Theme 3 leads: Prof. Peter Magill and Prof. Stephanie Cragg

Work in OPDC Theme 3 is directed by the principle that high-resolution mechanistic understanding of cell function and dysfunction in the context of neuronal circuits is the keystone of the translational bridge between ‘basic neuroscience’ and the clinic. The foundation for progress in Theme 3 is our established approach of longitudinal ‘deep phenotyping’ of rodent models that harbour human disease-relevant genetic alterations.

By delivering on our multidisciplinary research strategy, we gain new mechanistic insights into how Parkinsonian genetic burden impacts on molecules, cells, circuits and behaviours. Using this knowledge, we aim to provide a rational basis for the development of novel disease-modifying interventions, and following multiple pathways to translation, we will advance towards our goal of delivering proof-of-principle for new therapies for Parkinson’s disease.

We generate novel transgenic mouse and rat lines that are designed to recapitulate the genetic burden and early stages of Parkinson’s. These and other rodent models offer robust and physiologically-relevant models for addressing our research priorities, such as;

(1) understanding why certain types of nerve cell are more vulnerable in disease;
 
(2) defining the biochemical consequences of genetic variation and ageing;
 
(3) identifying how damage and loss of dopamine-producing nerve cells impacts on their targets elsewhere in the brain.
 
A fourth important aspect of Theme 3 research is the provision of in vivo testing platforms that can be used for evaluating the therapeutic utility of novel interventions that are designed to slow, halt or even reverse disease progression.

Several pathways are followed to exploit Theme 3 discoveries and resources for translation; some directly stem from new insights gained in animal models, while others are fed by research advances arising in OPDC Theme 1 and Theme 2.