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.

Automated summary

Parkinson's disease is the second most prominent neurodegenerative disease globally, characterized by dopaminergic cell loss in SNc. Energy deficiency is hypothesized as a common underlying cause of SNc cell loss in PD, with a comprehensive computational model proposed to understand the pathophysiology at the subcellular level. The study aims to investigate how deficits in energy substrates lead to ATP deficiency, which is believed to be a common factor underlying molecular-level pathological changes in PD.