Study Rationale:
Alpha-synuclein is a sticky protein that clumps in the brains of people with Parkinson's disease (PD). In pre-clinical models, alpha-synuclein clumps attract scores of CCR2-positive monocytes -- blood cells that play a role in inflammation -- from the blood into the brain. Once in the brain, monocytes can
become either macrophages or
dendritic cells, each of which have
properties and functions that are distinct
from microglia, immune cells that reside in the brain permanently. In this study, we will test whether monocyte entry into the brain is required for alpha-synuclein-induced inflammation and neurodegeneration. We will also test whether blocking their entry protects the brain from neurodegeneration mediated by alpha-synuclein.
Hypothesis:
We hypothesize that monocyte entry into the brain is key to alpha-synuclein-induced inflammation and neurodegeneration and that stopping monocytes from entering the brain protects it from alpha-synuclein-mediated neurodegeneration.
Study Design:
In this study, we aim to understand the role of monocytes that enter the brain and to determine whether their entry is necessary for inflammation and neurodegeneration caused by alpha-synuclein. We will first characterize the timing and extent of monocyte entry into the brain in response to alpha-synuclein clumps in pre-clinical models. Next, we will determine whether blocking CCR2 -- a protein on the monocyte surface that enables them to enter the brain -- protects against alpha-synuclein-induced death of dopamine-producing 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 models of Parkinson's disease with features of alpha-synuclein pathology.