It will be important to understand the functional consequence of familial PD-associated genes on microglia function and our data may offer an opportunity to identify common pathways for PD related to innate immune function, both in the CNS and the periphery. Anomalies in phagocytosis and cytokine release have been documented with various autoimmune-related diseases, however the consequence of similar defects on neurodegenerative processes is yet not established. While inflammatory cytokines have been shown to be elevated in the brains of PD patients, cytokine levels are usually measured at the mRNA level or as total protein levels in brain extracts and therefore do not delineate between secreted and intracellular cytokines. Additionally, reports assessing peripheral inflammatory responses in PD patients have been varied, with reports showing increased cytokines in PD serum, but decreased release of cytokines from PBMCs isolated from PD patients. In our in vitro system we demonstrate that elevated a-syn impairs the secretion of cytokines without altering inflammatory responses at the mRNA or total protein level, a defect that cannot be observed using pure analytical methodology since it cannot differentiate between intracellular and released cytokines. Misregulated cytokine release may cause chronically stressed and activated microglia, and contribute to perpetuating the inflammation and neurodegeneration seen in PD. Microglia release of critical neurotropic factors, such as NGF and BDNF and the general impact on vesicle secretion machinery by elevated levels of a-syn may be as important a contributor to disease as the alterations in inflammation. Previous studies have Lomitapide Mesylate identified defective mobilization of dopamine from the reserve vesicle pool in neurons of a-syn TG mice, and the culmination of numerous literature reports implicate a-syn as a negative regulator of vesicle trafficking/and or vesicle fusion. Although neuronal and inflammatory processes may appear distinct, the release of cytokine containing vesicles following an inflammatory insult is a process akin to the release of neurotransmitter containing synaptic vesicles following stimulation, utilizing similar SNARE machinery. Elevated a-syn levels have been shown to retard the release of Folinic acid calcium salt pentahydrate neurotransmitters, an outcome that could lead to progressive neurodegeneration, and our observations for immunologic functions provide another avenue by which a common mechanism for decreased vesicular function may lead to neurodegeneration. We demonstrated that increased a-syn disrupts the release of inflammatory mediators from microglia and macrophages, as well as the recruitment of vesicular components necessary to support a phagocytic response. Normal phagocytic function was restored after a-syn siRNA treatment, demonstrating a direct role for a-syn in these processes. Furthermore, using cell culture systems we were able to induce a similar phagocytic deficit by increased a-syn expression in H4 cells. Evoked cytokine release and phagocytosis are excellent model systems to study membrane and vesicle dynamics, as well as biological readouts of normal SNARE function. The reported relationship between a-syn and SNARE function has been mixed. Chandra et al. demonstrated that a-syn overexpression rescued the lethality and neurodegeneration observed in CSP-1 knockout animals. The authors hypothesized that a-syn was protective because it could act as a SNARE chaperone in the absence of the normal chaperone, CSP-1. This hypothesis has recently been confirmed, and it was demonstrated that a-syn binds to members of the SNARE complex to facilitate SNARE assembly.