Mitochondrial Dysfunction and Susceptibility to Parkinson's disease: New Models of Pathogenetic Interactions

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. It affects approximately 150,000-200,000 in the UK and that represents a significant burden in terms of reduced quality of life of patient and carer.

The cause of Parkinson's disease is not yet completely understood, but there are many insights into causes of familial Parkinson's disease which have provided valuable insight into those mechanisms that may result in the disease affecting the majority of people.

The genetic causes of Parkinson's disease include abnormalities of the PINKl gene. PINKl has been found to be involved in energy production within the cell, there is also response for other important processes such as the generation of free radicals.

This grant involves four laboratories in the world from the UK, Germany, Italy and Canada. All of which have a major focus of interest on PINKl function. They have come together to collaborate in their research to identify how PINKl deficiency makes individuals susceptible to the development of Parkinson's disease and how this deficiency might also interact with other genetic abnormalities that cause Parkinson's disease.

The focus is on identifying the sequence of molecular events, the results from PINKl deficiency to identify potential targets that may be suitable for drug intervention to slow or prevent progression of the PINKl related cell abnormalities. These targets will then be assessed in other models of Parkinson's disease and particularly for their suitability to be studied in idiopathic Parkinson's disease.

This is an interactive, four-team research project in which complementary expertise/resources will be shared to develop animal models that better mimic pathogenetic processes in Parkinson's disease (PD). We plan to generate and utilize novel in vivo models in which mitochondrial defects enhance susceptibility to PD-like pathology. The relevance of these models is twofold. First, clinical and experimental evidence points to mitochondrial abnormalities as a key player in PD pathogenesis. Second, PD pathogenesis is likely the result of multifactorial insults that could well be exacerbated by an underlying mitochondrial dysfunction. PINK1 deficiency in mice, which causes mitochondrial and calcium abnormalities in the absence of frank neurodegenerative changes, will model a "permissive" genetic background on which the effects of other genetic/toxic challenges will be evaluated. We will not only determine if these combined paradigms result in synergistic damage but also assess specific mechanistic hypotheses, such as the role of calcium homeostasis in neurodegeneration. From the technical side, an integral component of these studies will be the use of state of- the-art imaging techniques and the generation of reporter mice. In the spirit of this COEN initiative, studies will be conducted in parallel at the four sites, and foster opportunities for longer-term collaborative efforts.

All team leaders have discussed this topic and agreed that, should exploitable results be generated within this COEN project, applicants will first refer to the technology transfer offices at their institutions. For common discoveries, intellectual property issues will be discussed in good faith on a case-by-case basis.