2 years ago

2013 Scientific Report

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Patrik Brundin, M.D.,

Patrik Brundin, M.D., Ph.D. Laboratory for Translational Parkinson’s Disease Research Dr. Brundin earned both his M.D. and Ph.D. at Lund University, Sweden. He has over 30 years of experience with neurodegenerative diseases, has some 300 publications, and is in the top 0.5% of cited researchers in the field. Much of his research has addressed disease mechanisms in cell culture and animal models of Parkinson’s disease. In addition to managing laboratories at VARI and in Lund, Sweden, he is Associate Director of VARI and the co-editor-in-chief of the Journal of Parkinson’s Disease. From left: Kaufman, Beauvais, Brundin, Steiner, Cousineau, Ghosh Staff Genevieve Beauvais, Ph.D. Kim Cousineau, B.S. Martha Escobar, Ph.D. Anamitra Ghosh, Ph.D. Darcy Kaufman, M.S. Jennifer Steiner, Ph.D. 11

Van Andel Research Institute | Scientific Report Research Interests The Laboratory for Translational Parkinson’s Disease Research studies cellular and rodent models of neurodegenerative disease. We currently focus on several projects that might lead us to our ultimate goals of 1) understanding why Parkinson’s disease (PD) develops and 2) discovering new methods of treatment that could stop or slow disease progression. We expect that these experiments will reveal how genetic and other factors are associated with PD pathology. Many rodent models of PD are based on treating the animals with neurotoxins such as 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) or 6-hydroxydopamine. These toxins lead to select neuronal degeneration within days in brain areas relevant to PD. However, we know that the development of PD in humans is a decades-long process of neuron death, unlike the short time line of days in these models. We have initiated work in a mouse that lacks one copy of a gene known to be expressed in midbrain dopaminergic neurons and that exhibits a progressive degeneration of these cells. As a consequence, the neurons’ slow degeneration over many weeks into adulthood more closely mirrors PD. In our studies, we are carefully analyzing the morphological and neurochemical changes in the degenerating dopamine neurons and trying to understand the changes in gene expression in the cells during the process. We believe these mice will be a highly relevant model of PD, and we are now planning to treat them with potentially neuroprotective agents over several weeks in attempts to slow down the degenerative process. We are also using a transformed cell line derived from the immature human ventral midbrain. We can differentiate these cells into mature dopaminergic neurons that exhibit the expected electrical activity and synthesize dopamine. We have previously identified the sensitivity of these human midbrain neurons to cellular toxins or stresses. This unique dopaminergic cell line serves as a starting point for many of our studies with both neurotoxins and neuroprotective agents. We aim to determine whether known neuroprotective drugs, some of which are currently in clinical trials, rescue these dopaminergic cells from PD-relevant challenges. If these human cells respond positively to these drugs, then we will test the agents in the mouse models described earlier. For example, disturbances in mitochondrial function are hypothesized to play an important role in the development of PD. Therefore we will explore whether drugs that modulate mitochondrial function can protect against neurodegeneration. Our current experiments using the genetic mouse models and toxin-based mouse models of PD described above will help us decide whether these mitochondrial modulators may be efficacious in the clinic. In order to study how PD develops, we also study the spreading of abnormal a-synuclein (a-syn) protein. The transmission of a-syn-associated pathology from cell to cell throughout the nervous system is believed to drive the clinical disease state and underlie several PD symptoms, including nonmotor symptoms. We are interested in identifying the mechanisms underlying intercellular a-syn transfer and transport in order to clarify their role(s) in the development of PD. We will partly focus on inter/intracellular transfer involving exosomes. We plan to perform studies using exosomes isolated under specific conditions (e.g., overexpression of a-syn) to determine whether exosomes play a role in a-syn transfer and aggregation. We will also explore the fate of a-syn that has been taken up by neurons. Thus, we will attempt to clarify how the imported a-syn is processed inside the cells and under what conditions it is transported between brain regions in rodents. In addition, we plan to use Caenorhabditis elegans to identify genes that control a-syn transfer between cells. We will generate transgenic C. elegans strains that will allow us to study a-syn transfer between neurons with the help of fluorescent markers. 12

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