Description
Mechanistic investigation of Parkinson's disease risk factors: a common genetic variation in antigen presentation capacity and pesticide exposure
Elizabeth Kline1, Kathryn MacPherson1, George Kannarkat1, W. Michael Caudle2, Malú G. Tansey1
Department of Physiology1, Department of Environmental Health, Rollins School of Public Health2, Emory University, Atlanta, GA
Antigen presentation via major histocompatibility complex class II (MHCII) controls immune response to specific targets. In Parkinson's disease (PD), substantia nigra (SN) dopamine neurons are burdened with α-synuclein aggregates. Cells expressing MHCII have been identified within post-mortem SN of PD patients, often near dopamine (DA) neurons and α-synuclein (asyn) aggregates. rs3129882, a common single nucleotide polymorphism in the MHCII loci is associated with PD risk. Our group found that PD (high-risk, GG) patients exhibit a 300-fold greater inducible increase in MHCII mRNA compared to PD (AA). Thus, in PD, myeloid cells may contribute to neuroinflammation via antigen presentation.
To establish the effect of increased MHCII expression, we are evaluating CD4+ T helper subsets in the peripheral blood mononuclear cell population in healthy controls and PD patients (AA, GG, AG). We hypothesize that increased antigen presentation capacity via MHCII will skew the CD4+ subsets of GG individuals towards inflammatory Th1 phenotypes.
In order to better understand the interaction between MHCII and an asyn burden in the SN, we stereotaxically injected rAAV2/5-human WT asyn to the SN of mice lacking MHCII in peripheral myeloid cells. In a “double-hit”, gene-by-environment interaction model, we also dosed these mice with the pesticide cypermethrin. Epidemiological studies report a connection between pesticide exposure and the incidence of PD. In addition to direct effects on DA neurons, cypermethrin exposure may affect immune cell function and has been show to increase odds for PD in GG individuals. By flow cytometry, we are characterizing peripheral immune cells as well as cells from deep cervical lymph nodes, the meningeal lymphatics' draining lymph nodes, in our “double-hit” mice. Additionally, we are immunohistochemically examining asyn expression in the SN and markers of brain immune cell activation and T cell infiltration. We predict mice with peripheral myeloid MHCII deletion will be protected from inflammation and dopaminergic dysfunction induced by human asyn expression and cypermethrin treatment.