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Funded Studies

Investigating Kainate Receptor as a Potential Target to Protect against Early-Onset Parkinson's Disease

Study Rationale:
Kainate receptors (KARs) are proteins on the surface of neurons that help to transmit signals between the neurons. The process generates electrical currents at the point of transmission in the neurons that receive signals. Previous studies showed that part of the KAR protein interacts with the parkin, a protein that normally breaks down other, damaged proteins in a cell. If parkin doesn't function as it should, it stays bound to part of the KAR, which, in turn, increases electrical currents in neurons. This takes place in autosomal recessive juvenile parkinsonism (ARJP) and early-onset Parkinson's disease (PD) caused by changes (mutations) in the PARK2 gene. Studies have demonstrated increased KAR levels and/or corresponding electrical currents in cells with PARK2 mutations in the substantia nigra of pre-clinical models and in brains of people who have PARK2-associated PD.

KARs regulate neuron activity, and PARK2 mutations have been associated with increased KAR levels. We hypothesize that the PARK2 mutation can lead to KAR accumulation that kills dopamine-producing brain cells and leads to movement dysfunction. We aim to show that blocking KAR activity could help to protect neurons.

Study Design:
We will test genetic and pharmacological methods of blocking KAR, either partially or completely, to determine if it helps to protect neurons in pre-clinical models with a PARK2 mutation. We also will aim to confirm that KAR levels are different in models lacking parkin compared with models with normal parkin.

Impact on Diagnosis/Treatment of Parkinson's disease:
The results of this study will clarify whether KAR is a potential therapeutic target in early-onset Parkinson's or ARJP.

Next Steps for Development:
If our study reveals that blocking KAR has neuroprotective effects when a PARK2 mutation is present, investigators can develop treatments that target KAR and test them for safety and efficacy in individuals with PARK2-associated Parkinson's.


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