Mathematical modeling of the role of α-synuclein and dopamine in cell death in Parkinson’s disease provides the molecular basis to the toxicity of different point mutations

Abstract

Different types of -synuclein and non-{beta}-amyloid component (NAC) peptides have been shown to induce cell death, with varying degree of toxicity, in various in vitro experiments. Oxidative stress has also been associated and proved to be involved in the pathogenesis of neuronal cell death in Parkinsons disease. Oxidative stress has been shown to accelerate the aggregation of -synuclein in vitro and in resent studies -synuclein has been shown to increase oxidative stress. Thus it seems like a vicious cycle, one promoting the other.\n\nIn this present work we have modeled the -synuclein pathway to increase cytoplasmic Dopamine concentration, and thereby increasing the Reactive Oxygen Species (ROS) level of the cell, which consequently results in cell death. This model relates the -synuclein concentration with the fractional cell survival and provides insight of crucial reaction(s) of -synuclein which promote cell death. It predicts the toxicity of the type of -synuclein and also explains the pattern of cell death with increasing concentration of -synuclein. First we modeled a part of the pathway i.e. from dopamine to cell death. The results were compared with experimental data available for PC12 neuronal cell line. Then modeling of full pathway was done and the results were compared with experimental data available for Human neuroblastoma SH-SY5Y cells. It is predicted from this model that higher the auto catalysis of dopamine, higher is the cell death. Interestingly, the model predicts that NAC (1-18) not only hinders the vesicles coming from Endoplasmic Reticulum, to fuse with Golgi bodies, but also reduces the synthesis of Dopamine and the formation of vesicles from Endoplasmic Reticulum. The model is generalized and can predict the toxicity of any protein which impedes the early secretary pathway in dopaminergic cells and also the cell survival pattern with increasing concentration of the protein.