Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration.

Parkinson's 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 the subcellular level in PD. The aim of the study is to see how deficits in the supply of energy substrates (glucose and oxygen) lead to a deficit in adenosine triphosphate (ATP). The study also aims to show that deficits in ATP are the common factor underlying the molecular-level pathological changes, including alpha-synuclein aggregation, reactive oxygen species 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 modeling framework to understand the neurodegenerative processes underlying PD.