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University of Ottawa Faculty of Medicine Researchers Uncover New Targets for Parkinsonís and Alzheimerís Treatment

OTTAWA — A recent study by the laboratory of Dr. David Park, assistant dean of research at the University of Ottawa’s Faculty of Medicine, has uncovered a link between a protein known as Cdk5 and DNA damage/repair in neurons. The findings, together with their implications for neurodegenerative diseases such as Parkinson’s and Alzheimer’s, were recently published in the prestigious journal Nature Cell Biology.

In collaboration with the laboratories of Drs. Ruth Slack (University of Ottawa) and John Woulfe (Ottawa Hospital Research Institute), Dr. Park’s laboratory has shown that the disruption of the Cdk5-Ape1 pathway results in accumulation of DNA damage, which ultimately causes neurons to die. The labs have taken the findings one step further by showing that these pathways are disrupted in the brains of Parkinson’s and Alzheimer’s patients.

DNA damage and defects in the pathways involved in DNA repair can result in neuron death and have been implicated in a number of neurodegenerative diseases. As such, neuroscience researchers have become increasingly interested in understanding these pathways and identifying downstream factors that may represent important targets for drug development.

“We have identified what we believe is a critical disruption in the signaling pathway that may cause neurons to die by a variety of means, as in Parkinson’s and Alzheimer’s disease. We have shown that on this pathway an important DNA repair mechanism is shut down as neurons experience stress. Inappropriate hyper-activation of Cdk5, a protein normally found in neurons, leads to loss of function of a DNA repair enzyme called APE1. This leads to increased DNA damage and neuron death", says Dr. Park.

The findings provide the first direct link between Cdk5 and the pathological mechanisms of neurodegenerative disease. Furthermore, this discovery opens up the possibility of designing drugs to target this pathway in order to reduce neuron death in neurodegenerative diseases such as Parkinson’s and Alzheimer’s.

The research work was supported by Parkinson Society Canada, the Parkinson’s Disease Foundation, the Parkinson’s Research Consortium, the Heart and Stroke Foundation of Ontario, the Canadian Institutes of Health Research, Brain Repair Program - Neuroscience Canada, and the World Class University Project (National Research Foundation, Ministry of Education, Science and Technology, South Korea).

The full manuscript, titled The role of Cdk5-mediated apurinic/apyrimidic endonuclease 1 phosphorylation in neuronal death, can be found in the latest edition of Nature Cell Biology (Nat Cell Biol. 2010 Jun;12(6):563-71).

Source Date: Jun 26 2010