COEN

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 two-fold. 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 longerterm collaborative efforts.

Specific objectives
a. To determine if PINK1 deficiency renders animals more susceptible to further damaging events
b. To test the hypothesis that mitochondrial dysfunction and lysosomal storageabnormalities act together in triggering or enhancing PD-like pathology
c. To test the hypothesis that perturbation of calcium homeostasis is a key mechanismlinking mitochondrial defects to dopaminergic cell degeneration in PINK1 deficient mice
d. To test the hypothesis that Letm1 (leucine zipper-EF-hand containing transmembrane protein 1), a mitochondrial calcium/H antiporter, mediates calcium dysregulation in PINK1-deficient mice.
e. To generate a new line of reporter mice in which to investigate the relationship between oxidative stress and mitochondrial calcium perturbation
Partners
1. DZNE, Bonn, Germany (Donato A. Di Monte, coordinator)
2. University of Ottawa – CIHR, Canada (David S. Park)
3. IRCCS National Neurological Institute C. Mondino – Ministry of Health, Italy (Fabio Blandini)
4. Department of Clinical Neurosciences, MRC – University College London, UK (Anthony H.V. Schapira)

Duration: 24 months
Start date: 1 January 2012

The COEN initiative (www.coen.org)
In 2010, the Canadian Institutes of Health Research (CIHR), the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE, Germany) and the Medical Research Council (MRC, UK) launched a funding initiative to establish collaborative activity between national centres of excellence in research into neurodegenerative disorders. These founding members were joined, shortly after, by VIB (Flanders Institute for Biotechnology), the Health Research Board/Science Foundation Ireland (HRB/SFI), and the Ministry of Health Italy (Ministero della Salute, MDS). The aim of the initiative is to build productive links between research groups within recognised centres of excellence in neurodegeneration, in partner countries, in order to add value to investments and accelerate progress in understanding the mechanisms of disease as well as the identification of new therapeutic approaches. The first call for proposals was launched on February 2011.