Elevated levels of Reactive Oxygen Species (ROS) and accumulation of misfolded α-synuclein (αSYN) are recurrent features in a majority of Parkinson's Disease cases. Building on the brain energy metabolism framework in Chapter 2, a mathematical model is constructed of these key neurochemical players and their interactions. A computer implementation of the model is used to simulate and visualise the dynamics of ROS, αSYN and their non-linear interaction within a positive feedback loop. The most important observation from this modelling is that the homogenous nature of known biomarkers (ROS/αSYN) can be reconciled with the heterogeneous nature of the underlying risk factors, including aging, genetics and toxins. More specifically, our model uses risk factors (aging, toxins) as 'inputs' and then provides estimates of PD susceptibility based on their propensity to destabilise the model system. The stability of the model is then used as a criterion to quantify the level of various risks. The importance of rapid biochemical dynamics in evaluating the impact of neuroprotective strategies is also highlighted, with simulations demonstrating the synergistic effect of creatine and anti-oxidants in buffering ROS levels during transient conditions.
Paru en décembre 2012 , 21 pages