Interaction of Synuclein and Inflammation in Dopaminergic Neurodegeneration

Abstract : Parkinson Disease (PD) is the second most common neurodegenerative disease of our aged population behind Alzheimer s Disease. Epidemiological, animal and cell culture studies have shown that inflammation is a part of the PD morphological picture. It has been suggested that -synuclein (a major component of the Lewy bodies present within dopamine neurons of the PD substantia nigra {SN}) is responsible for the observed inflammatory response in the PD brain. We injected -synuclein and mutated synuclein into the substantia nigra (SN) of rats (8 ug/4ul). We also performed cell culture studies on the activation of microglia by alpha-synuclein. In our in vivo studies, we found that both alpha-synuclein and A53T mutated synuclein both caused apomorphine-induced rotations. The number of rotations were small but significant and indicates that the synucleins caused an increase in sensitivity of the dopaminergic (DA) receptors in the SN. These studies indicate that there is some interaction between DA and the synucleins. In our in vitro studies, we noted that the synucleins caused microglia to adhere to plastic surfaces. This adhesion was blocked by EDTA which indicated that the process of adhesion in this case was calcium-dependent. In our examination of cell migration using various synucleins, we found that only LTB4, a leukotriene, and CX3CL1, a chemokine, enticed microglia to migrate to naked or laminin-coated filters. While we cannot conclude from our cell culture studies that synucleins can trigger neuroinflammation, we can state that the synucleins can activate microglia and cause them to migrate.