TY - JOUR
T1 - Dysregulated biodynamics in metabolic attractor systems precede the emergence of amyotrophic lateral sclerosis
AU - Curtin, Paul
AU - Austin, Christine
AU - Curtin, Austen
AU - Gennings, Chris
AU - Figueroa-Romero, Claudia
AU - Mikhail, Kristen A.
AU - Botero, Tatiana M.
AU - Goutman, Stephen A.
AU - Feldman, Eva L.
AU - Arora, Manish
N1 - Publisher Copyright:
© 2020 Curtin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/4
Y1 - 2020/4
N2 - Evolutionarily conserved mechanisms maintain homeostasis of essential elements, and are believed to be highly time-variant. However, current approaches measure elemental biomarkers at a few discrete time-points, ignoring complex higher-order dynamical features. To study dynamical properties of elemental homeostasis, we apply laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) to tooth samples to generate 500 temporally sequential measurements of elemental concentrations from birth to 10 years. We applied dynamical system and Information Theory-based analyses to reveal the longest-known attractor system in mammalian biology underlying the metabolism of nutrient elements, and identify distinct and consistent transitions between stable and unstable states throughout development. Extending these dynamical features to disease prediction, we find that attractor topography of nutrient metabolism is altered in amyotrophic lateral sclerosis (ALS), as early as childhood, suggesting these pathways are involved in disease risk. Mechanistic analysis was undertaken in a transgenic mouse model of ALS, where we find similar marked disruptions in elemental attractor systems as in humans. Our results demonstrate the application of a phenomological analysis of dynamical systems underlying elemental metabolism, and emphasize the utility of these measures in characterizing risk of disease.
AB - Evolutionarily conserved mechanisms maintain homeostasis of essential elements, and are believed to be highly time-variant. However, current approaches measure elemental biomarkers at a few discrete time-points, ignoring complex higher-order dynamical features. To study dynamical properties of elemental homeostasis, we apply laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) to tooth samples to generate 500 temporally sequential measurements of elemental concentrations from birth to 10 years. We applied dynamical system and Information Theory-based analyses to reveal the longest-known attractor system in mammalian biology underlying the metabolism of nutrient elements, and identify distinct and consistent transitions between stable and unstable states throughout development. Extending these dynamical features to disease prediction, we find that attractor topography of nutrient metabolism is altered in amyotrophic lateral sclerosis (ALS), as early as childhood, suggesting these pathways are involved in disease risk. Mechanistic analysis was undertaken in a transgenic mouse model of ALS, where we find similar marked disruptions in elemental attractor systems as in humans. Our results demonstrate the application of a phenomological analysis of dynamical systems underlying elemental metabolism, and emphasize the utility of these measures in characterizing risk of disease.
UR - http://www.scopus.com/inward/record.url?scp=85083477163&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1007773
DO - 10.1371/journal.pcbi.1007773
M3 - Article
C2 - 32294079
AN - SCOPUS:85083477163
SN - 1553-734X
VL - 16
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 4
M1 - e1007773
ER -