Zucchi, E;
Lu, C-H;
Cho, Y;
Chang, R;
Adiutori, R;
Zubiri, I;
Ceroni, M;
... Petzold, A; + view all
(2018)
A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry.
Journal of Neurochemistry
, 146
(5)
pp. 631-641.
10.1111/jnc.14542.
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Abstract
Neurofilament proteins (Nf) are a biomarker of disease progression in amyotrophic lateral sclerosis (ALS). This study investigated whether there are major differences in expression from in vivo measurements of neurofilament isoforms, from the light chain, NfL (68 kDa), compared to larger proteins, the medium chain (NfM, 150 kDa) and the heavy (NfH, 200-210 kDa) chains in ALS patients and healthy controls. New immunological methods were combined with Nf subunit stoichiometry calculations and Monte-Carlo simulations of a coarse-grained Nf brush model. Based on a physiological Nf subunit stoichiometry of 7:3:2 (NfL:NfM:NfH) we found an "adaptive" Nf subunit stoichiometry of 24:2.4:1.6 in ALS. Adaptive Nf stoichiometry preserved NfL gyration radius in the Nf brush model. The energy and time requirements for Nf translation were 56±27k ATP (5.6 hours) in control subjects compared to 123±102k (12.3 h) in ALS with "adaptive" Nf stoichiometry (not significant) and increased significantly to 355±330k (35.5 h) with "luxury" Nf subunit stoichiometry (p<0.0001 for each comparison). Longitudinal disease progression related energy consumption was highest with a "luxury" Nf stoichiometry. Therefore, an energy and time saving option for motor neurons is to shift protein expression from larger to smaller (cheaper) subunits, at little or no costs on a protein structural level, to compensate for increased energy demands. This article is protected by copyright. All rights reserved.
| Type: | Article |
|---|---|
| Title: | A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/jnc.14542 |
| Publisher version: | https://doi.org/10.1111/jnc.14542 |
| Language: | English |
| Additional information: | © 2018 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | ALS, energy, neurodegeneration, neurofilaments, stoichiometry |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10051512 |
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