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Mitochondrial dysfunction and neuronal demise: Insights provided by Parkinson’s disease genes

 

Team
Principal Investigator: Dr. Louis-Eric Trudeau
Team Members: Dr. Ted Fon, McGill University
Dr. Yong Rao, McGill University
Dr. David Park, University of Ottawa
Dr. Heidi McBride, University of Ottawa
Dr. Michael Schlossmacher, University of Ottawa

Project Overview
Converging research efforts have recently identified five genes that are associated with familial Parkinson’s Disease (PD), a condition associated with severe motor dysfunction and loss of dopamine-producing cells in the brain. These genes include α-synuclein, Parkin, DJ-1, Pink1, LRRK2. It is striking that all of them have been linked directly or indirectly with the function of mitochondria, small ubiquitous intracellular organelles found in all cells. A research group, led by Dr. Louis-Eric Trudeau from the Université de Montréal undertook collaborative projects to systematically examine PD genes and their control of mitochondrial function and neuronal physiology and survival.

Findings
The team focused their attention on the impact of LRRK2, DJ-1, Pink1 and Parkin gene mutations on the function of mitochondria and on the function of neurons, and, in particular dopamine-secreting neurons in the brain. Experiments were performed in mouse neurons as well as in the fly, Drosophila, a unique and powerful model system. Drs. Yong and Park have been developing new approaches to knockdown the function of these genes in the fly and developing behavioural assays to monitor the functional impact. Drs. Park and McBride have been expanding on their recent efforts to develop approaches to monitor multiple readouts of mitochondrial function. Drs. Fon, Trudeau and Schlossmacher have been concentrating their initial efforts on the Parkin gene and are evaluating the impact of its gene deletion on mitochondrial function and dopamine neuron physiology as well as studying the proteins that it interacts with and the regulation of its expression. These studies have led to exciting observations, many of which have now been published in international journals, with many other publications to come during the upcoming year.

After three years of fruitful collaboration, the group has achieved great progress in its objectives to evaluate the impact of LRRK2, DJ-1, Pink1 and Parkin genes mutations on the function of mitochondria and on the function of neurons and in particular dopamine-secreting cells of the brain.

Publications
The Journal of Neuroscience, December 15, 2010
Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4–CHOP-Mediated Induction of 
the Bcl-2 Homology 3-Only Member PUMA

Human Molecular Genetics, July 2010, Vol. 19
Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics

Nature Cell Biology, Volume 12 | Number 6 | June 2010 -
The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death