The main objective is to identify inflammatory signaling mechanisms in Parkinson disease (PD), and validate them as potential targets for neuroprotective therapies.
Inflammation of the brain has long been recognized as a feature of Parkinson disease. This inflammation is marked by activation of microglia, the resident immune cells of the nervous system, expression of pro-inflammatory cytokines and by the influx of immune cells from outside the brain, particularly B and T lymphocytes. Recently researchers have recognized that this inflammation may occur early in PD and thus play a key role in neurodegeneration. These studies aim to identify how alpha-synuclein, the primary protein implicated in Parkinson disease pathogenesis, contributes to microglial activation and activation of the innate and adaptive immune response. This novel approach suggests that, while there may be several upstream triggers for PD, once the degenerative process starts, it is inflammation that is responsible for progression.
We have developed an animal model in which we have a targeted overexpression of alpha-synuclein in the substantia nigra via an adeno-associated virus (AAV-SYN). This animal model demonstrates many of the key features of inflammation seen in human PD prior to dopaminergic neuron loss. We are using the AAV-SYN model to explore the mechanisms of inflammation that lead to neurodegeneration, and to identify potential immunologic targets for neuroprotective treatment. For example, studies from our lab have shown that both FcγRs and MHCII are required for inducing neuroinflammation and dopaminergic neurodegeneration in the AAV-SYN model. These studies are intended to lay the groundwork for an understanding of the mechanisms that trigger and sustain inflammation in PD.
