Of these 7, genome-wide studies have associated RIT2 and ANK1 with Parkinson’s and Alzheimer’s disease respectively. This shared property of differential IFN-c co-expression suggests a possible grouping of cases based on disruptions of RIT2, ANK1 and SNCA. Immunity is a major factor in Parkinons’s disease progression and immunomodulary therapies are being explored. In agreement with our results, several human studies have linked IFN-c to PD. Mount and colleagues report elevated blood plasma levels of IFN-c in PD patients. Genetically, a large number of the IFN-c signaling genes are in the HLA histocompatibility region which harbors common variants that have been associated with PD. Another PD risk gene, LRRK2, is suspected to be an IFN-c target gene. Epidemiological studies have found that cigarette smoking and coffee consumption confer reduced PD risk and both reduce levels of IFN-c production. More directly, use of nonsteroidal anti-inflammatory drugs are associated with decreased risk of PD. At the cellular level, a fluorescence microscopy study of human derived glioblastomal cells treated with IFN-c revealed a reduction of peripheral SNCA at low doses and aggregation after high concentration treatment of IFN-c. Although observed in malignant cells, this reduction in SNCA after low doses of IFN-c parallels our negative co-expression observation in normal brain. The high dose response, like our findings in Parkinson’s cases, shows that the interaction CHIR-99021 between SNCA and IFN-c is variable. Kim and colleagues have noted dual roles of SNCA: neuroprotection and neurotoxicity. In addition, SNCA risk genotypes were found to have a dual and opposing associations with Parkinson’s symptom scores. Our findings suggest IFN-c signaling may provide these roles. Experiments in mice have provided causal connections between IFN-c and features of Parkinson’s that inform the correlations we found in postmortem brains samples. Specifically, the MHCII complex is required for microglia activation by SNCA expression. Overexpression of IFN-c causes neuronal loss primarily in the nigrostriatal tract and basal ganglia calcification. Several PD-like features were reduced in IFN-c deficient mice. In vitro, IFN-c treatment causes microglia dependent death of dopamine neurons and mice treated with an IFN-c neutralizing antibody had reduced rotenone-induced neuronal loss. In Parkinsonian monkeys, IFN-c levels correlated with motor impairment, microglia activation and damage to the substantia nigra. Studies examining IFN-c and SNCA interactions are lacking but in vitro studies suggest that microglia activation is modulated by SNCA. Microglia cultures from SNCA knockout mice show increased activation and cytokine secretion. These findings suggest interactions between SNCA and microglia via IFN-c that are more direct than the response to SNCA aggregates. In agreement with others, our results suggest that therapeutic reduction of SNCA in PD may initiate unwanted changes in microglia phenotype and Parkinson’s symptoms. Our results combined with past observations in human and experiments in mouse and monkey.