INFLUENCE OF ENERGY DEFICIENCY ON THE MOLECULAR PROCESSES OF SUBSTANTIA NIGRA PARS COMPACTA CELL FOR UNDERSTANDING PARKINSONIAN NEURODEGENERATION: A COMPREHENSIVE BIOPHYSICAL COMPUTATIONAL MODEL

Abstract

Parkinsons disease (PD) is the second most prominent neurodegenerative disease around the world. Although it is known that PD is caused by the loss of dopaminergic cells in substantia nigra pars compacta (SNc), the decisive cause of this inexorable cell loss is not clearly elucidated. We hypothesize that "Energy deficiency at a sub-cellular/cellular/systems level can be a common underlying cause for SNc cell loss in PD." Here, we propose a comprehensive computational model of SNc cell which helps us to understand the pathophysiology of neurodegeneration at subcellular level in PD. The proposed model incorporates a rich vein of molecular dynamics related to SNc neurons such as ion channels, active pumps, ion exchangers, dopamine turnover processes, energy metabolism pathways, calcium buffering mechanisms, alpha-synuclein aggregation, Lewy body formation, reactive oxygen species (ROS) production, levodopa uptake, and apoptotic pathways. The proposed model was developed and calibrated based on experimental data. The influx of glucose and oxygen into the model was controlled, and the consequential ATP variations were observed. Apart from this, the dynamics of other molecular players (alpha-synuclein, ROS, calcium, and dopamine) known to play an important role in PD pathogenesis are also studied. The aim of the study was to see how deficits in supply of energy substrates (glucose and oxygen) lead to a deficit in ATP, and furthermore, deficits in ATP are the common factor underlying the pathological molecular-level changes including alpha-synuclein aggregation, ROS formation, calcium elevation, and dopamine dysfunction. The model suggests that hypoglycemia plays a more crucial role in leading to ATP deficits than hypoxia. We believe that the proposed model provides an integrated modelling framework to understand the neurodegenerative processes underlying PD.