Inflammation contributes to the degeneration of neurons in the brains of people with Parkinson’s disease (PD). One of the molecules involved in this inflammatory response is Complement Protein 5a (C5a). This inflammatory protein activates immune cells, such as the brain’s microglia, by binding to receptor proteins on the cell surface. We have found that — in pre-clinical models of PD or in isolated human cells — blocking the interaction of C5a with its receptor diminishes the activity of genes and proteins that drive brain inflammation and neurodegeneration in PD. We will now use genetically engineered cells derived from people with PD to determine whether targeting C5a activity can reduce or halt the brain inflammation and neurodegeneration in human PD.
We hypothesize that excessive production or activation of C5a can trigger neurodegeneration in PD. Drugs that inhibit this protein should therefore diminish the activation of microglia and the production of other inflammatory molecules that lead to neurodegeneration in people with PD.
In this study, we use techniques in genome engineering to generate microglia and dopamine-producing neurons derived from the cells of people with PD. We will determine whether stimulation of C5a triggers microglia activation, the production of pro-inflammatory immune molecules, and neuronal cell death. In parallel experiments, we will expose these cells to drugs that block the interaction of C5a with its receptor and assess whether this treatment can slow or stop the inflammation and neurodegeneration characteristic of PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
C5a and its receptor are attractive targets for therapeutic intervention in several inflammatory diseases. In isolated human cells and a pre-clinical model of PD, interfering with this protein-receptor pair decreases the production of pro-inflammatory immune molecules production and the loss of neurons, suggesting that targeting C5a could be valuable for the treatment of PD.
Next Steps for Development:
Drugs that interfere with the interaction of C5a and its receptor are currently in Phase III clinical trials or are being used to treat other disorders. With this data on their safety, these drugs should therefore be promising candidates for slowing or reversing the neurological complications of PD.