Studying Monocyte Entry into the Brain in Alpha-synuclein-induced Parkinson's Disease (supplement)

Study Rationale:
In the past, we demonstrated that entry of CCR2-positive monocytes into the brain is required for alpha-synuclein-induced inflammation and neurodegeneration in a model of Parkinson's disease (PD) with alpha-synuclein features. We genetically engineered the models to lack CCR2, a protein on the monocyte surface that enables them to enter the brain. Using these models, we showed that stopping monocyte entry attenuates alpha-synuclein-induced inflammation and neurodegeneration. While removing CCR2 provided neuroprotection, it was not clear whether targeting CCR2 with drugs to keep monocytes out of the brain would be protective against alpha-synuclein-induced inflammation and neurodegeneration.

Hypothesis:
We hypothesize that blocking the function of CCR2 with the RO5234444 drug will attenuate alpha-synuclein-induced inflammation and neurodegeneration in a model of Parkinson's with alpha-synuclein features.

Study Design:
In this study, we aim to examine whether blocking entry of CCR2-positive monocytes with RO5234444 attenuates alpha-synuclein-induced inflammation and neurodegeneration in a model of Parkinson's with alpha-synuclein features. We will use sophisticated research techniques, such as confocal microscopy, flow cytometry and unbiased stereology, to detect immune cells and inflammation inside the brain and to evaluate the loss of brain cells.

Impact on Diagnosis/Treatment of Parkinson's disease:
Novel drugs targeting CCR2 are making their way through clinical trials. It is important to study CCR2 in a model of Parkinson's to assess effects of blocking this target on alpha-synuclein-induced brain inflammation and toxicity.

Next Steps for Development:
The next steps for clinical development would be to test compounds that counteract CCR2 in other pre-clinical models of Parkinson's disease.