Study Rationale:
Microglia, an immune cell in the brain, takes up unneccessary alpha-synuclein proteins and passes it on to the major histocompatibility complex (MHCII). This involves an interaction between microglia and CD4 T cells, which leads to inflammation that can damage neurons (i.e., brain cells). Our previous data has shown that targeting MHCII protects neurons in a pre-clinical model of Parkinson's. But we don't yet know if targeting CD4 T cells would be effective at reducing inflammation and related damage to neurons.
Hypothesis:
We hypothesize that genetically blocking CD4 T cells will be protective against inflammation and neuron loss in a pre-clinical model of Parkinson's disease with alpha-synuclein features.
Study Design:
The goal of these studies is to examine, for the first time, whether blocking CD4 T cells using genetic strategies will reduce inflammation and neuron loss in an alpha-synuclein model of Parkinson's. To determine if blocking CD4 T cells entry is protective, we will perform histology and confocal microscopy, mononuclear cell isolation and flow cytometry to detect immune cell infiltration and inflammation, and unbiased stereology to determine cell loss.
Impact on Diagnosis/Treatment of Parkinson's disease:
Novel T cell therapeutics are making their way through clinical trials for disorders including multiple sclerosis. It is important to assess whether strategies that target T cells are protective against alpha-synuclein-induced inflammation and neuronal cell loss in Parkinson's.
Next Steps for Development:
The next steps for development would be to test T cell inhibitors or neutralizing antibodies in alpha-synuclein models of Parkinson's disease.