A Systems Model of Parkinson's Disease Using Biochemical Systems Theory

OMICS. 2017 Aug;21(8):454-464. doi: 10.1089/omi.2017.0056.

Abstract

Parkinson's disease (PD), a neurodegenerative disorder, affects millions of people and has gained attention because of its clinical roles affecting behaviors related to motor and nonmotor symptoms. Although studies on PD from various aspects are becoming popular, few rely on predictive systems modeling approaches. Using Biochemical Systems Theory (BST), this article attempts to model and characterize dopaminergic cell death and understand pathophysiology of progression of PD. PD pathways were modeled using stochastic differential equations incorporating law of mass action, and initial concentrations for the modeled proteins were obtained from literature. Simulations suggest that dopamine levels were reduced significantly due to an increase in dopaminergic quinones and 3,4-dihydroxyphenylacetaldehyde (DOPAL) relating to imbalances compared to control during PD progression. Associating to clinically observed PD-related cell death, simulations show abnormal parkin and reactive oxygen species levels with an increase in neurofibrillary tangles. While relating molecular mechanistic roles, the BST modeling helps predicting dopaminergic cell death processes involved in the progression of PD and provides a predictive understanding of neuronal dysfunction for translational neuroscience.

Keywords: Parkinson's disease; biochemical systems theory; biomarkers; cell death; systems modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / analogs & derivatives
  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Biomarkers / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Cell Death
  • Computer Simulation
  • Disease Progression
  • Dopamine / metabolism*
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Gene Expression Regulation
  • Humans
  • Models, Statistical*
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Stochastic Processes
  • Systems Theory*
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • Biomarkers
  • MAPT protein, human
  • Reactive Oxygen Species
  • alpha-Synuclein
  • tau Proteins
  • 3,4-Dihydroxyphenylacetic Acid
  • 3,4-dihydroxyphenylacetaldehyde
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Dopamine