The frontline pharmacological treatment for Parkinson's disease is associated with serious side effects, creating a need for new therapeutic strategies. Recent evidence suggests that selective blockade of one glutamate receptor subtype (receptors containing the NR2D subunit) may be a useful treatment for Parkinson's disease.
The NR2D subunit is expressed in key brain structures that are affected during Parkinson's disease, and selective inhibition of these receptors may have therapeutic benefit via several potentially synergistic actions. For example reduction of glutamate receptor function might reduce the overactivation of three different sets of neurons in Parkinson's patients, which could synergize to reduce Parkinsonian symptoms. In addition, blockade of NR2D-containing glutamate receptors may slow the disease progression by reducing death in neurons that synthesize and release dopamine.
The goal of the proposed experiments is to identify small molecules that are subunit-selective inhibitors for eventual testing in animal models of Parkinson's disease. Validation that blockade of this receptor system could be beneficial in Parkinson's disease.
Final Outcome
Dr. Traynelis developed an assay that can identify compounds that enhance or reduce signaling through the NR2D receptor and identified several allosteric potentiators. He received supplemental funding to perform a larger compound screen with his newly developed assay to identify compounds that could suppress NR2D signaling. Promising candidate compounds will then be further tested and optimized.