A multistationary loop model of ALS unveils critical molecular interactions involving mitochondria and glucose metabolism

PLoS One. 2020 Dec 17;15(12):e0244234. doi: 10.1371/journal.pone.0244234. eCollection 2020.

Abstract

Amyotrophic lateral sclerosis (ALS) is a poor-prognosis disease with puzzling pathogenesis and inconclusive treatments. We develop a mathematical model of ALS based on a system of interactive feedback loops, focusing on the mutant SOD1G93A mouse. Misfolded mutant SOD1 aggregates in motor neuron (MN) mitochondria and triggers a first loop characterized by oxidative phosphorylation impairment, AMP kinase over-activation, 6-phosphofructo-2-kinase (PFK3) rise, glucose metabolism shift from pentose phosphate pathway (PPP) to glycolysis, cell redox unbalance, and further worsening of mitochondrial dysfunction. Oxidative stress then triggers a second loop, involving the excitotoxic glutamatergic cascade, with cytosolic Ca2+ overload, increase of PFK3 expression, and further metabolic shift from PPP to glycolysis. Finally, cytosolic Ca2+ rise is also detrimental to mitochondria and oxidative phosphorylation, thus closing a third loop. These three loops are overlapped and positive (including an even number of inhibitory steps), hence they form a candidate multistationary (bistable) system. To describe the system dynamics, we model the interactions among the functional agents with differential equations. The system turns out to admit two stable equilibria: the healthy state, with high oxidative phosphorylation and preferential PPP, and the pathological state, with AMP kinase activation, PFK3 over expression, oxidative stress, excitotoxicity and MN degeneration. We demonstrate that the loop system is monotone: all functional agents consistently act toward the healthy or pathological condition, depending on low or high mutant SOD1 input. We also highlight that molecular interactions involving PFK3 are crucial, as their deletion disrupts the system's bistability leading to a single healthy equilibrium point. Hence, our mathematical model unveils that promising ALS management strategies should be targeted to mechanisms that keep low PFK3 expression and activity within MNs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Disease Models, Animal*
  • Glucose / metabolism*
  • Glycolysis
  • Humans
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Models, Theoretical*
  • Mutation*
  • Oxidative Phosphorylation
  • Oxidative Stress
  • Superoxide Dismutase-1 / physiology*

Substances

  • Superoxide Dismutase-1
  • AMP-Activated Protein Kinases
  • Glucose

Grants and funding

Study financially supported by the Italian Ministry of Education, University and Research (SIR project n.RBSI14B1Z1) (MM), the Fondazione Compagnia di San Paolo (project n.2018.AAI629.U730/SD/pv) (GB), and the Motor Neurone Disease Association (project n. April16/848-791) (GB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.