Single-cell comprehensive biophysical model of SN pars compacta (Muddapu & Chakravarthy 2021)

Parkinson’s disease (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. We were able to show 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 also 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.

Model Type: Neuron or other electrically excitable cell

Region(s) or Organism(s): Basal ganglia

Cell Type(s): Substantia nigra pars compacta DA cell

Currents: Ca pump; I A, slow; I Ca,p; I Calcium; I h; I K,Ca; I K; I Na, leak; I_Na,Ca; I_SERCA; Na/Ca exchanger; Kir

Receptors: NMDA; AMPA

Transmitters: Dopamine; Glutamate; Gaba

Model Concept(s): Apoptosis; Action Potentials; Activity Patterns; Calcium dynamics; Detailed Neuronal Models; Homeostasis; Neurotransmitter dynamics; Pacemaking mechanism; Oscillations; Parkinson's; Pathophysiology

Simulation Environment: MATLAB; MATLAB (web link to model)

Implementer(s): Muddapu, Vignayanandam R. [vignan.0009 at]; Chakravarthy, Srinivasa V. [schakra at]


Muddapu VR, Chakravarthy VS. (2021). Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration. Scientific reports. 11 [PubMed]

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