New approaches to study Parkinson's disease

Marie-Francoise Chesselet, M.D., Ph.D.

University of California, Los Angeles

Parkinson’s disease (PD) is a neurodegenerative disorder that affects multiple brain areas, including the nigrostriatal dopaminergic neurons and results in an array of symptoms ranging from sleep disorders, anxiety, poor balance, and loss of smell to the more characteristic akinesia, rigidity, and tremor. The cause of PD is unknown but environmental factors combined to susceptibility genes are believed to play a role. Mutations responsible for rare familial forms of the disease have recently been identified and provide a way to identify relevant mechanisms in a number of model systems, including cells, flies and mice. Our laboratory specializes in the identification of mechanisms by which PD-causing mutations alter behavior and molecular mechanisms in mice, and cause brain pathology in these animals. We have shown that mice overexpressing alpha-synuclein, a vesicular protein associated with familial forms of PD and that accumulates abnormally in neurons in sporadic forms of the disease, express a constellation of symptoms and pathology similar to those seen in patients although they do not lose nigrostriatal neurons.  We are using a variety of approaches to identify the mechanisms causing dysfunction of these neurons, which may precede their loss in patients. We also use DNA microarrays to identify mechanisms that may protect the neurons in these mice and represent therapeutic avenues. In parallel, we are examining mechanisms by which pesticides, an environmental risk factor for PD, contribute to the pathology. Our goal is to provide a mechanistic understanding of the progression of dysfunction in neuronal systems affected in PD to identify therapeutic targets for neuroprotection, and a battery of model organisms and biomarkers to test these therapies in preclinical and clinical studies.