A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry.

Elisabetta Zucchi, Ching-Hua Lu, Yunju Cho, Rakwoo Chang, Rocco Adiutori, Irene Zubiri, Mauro Ceroni, Cristina Cereda, Orietta Pansarasa, Linda Greensmith, Andrea Malaspina, Axel Petzold

Journal of neurochemistry 2018 Sep

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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 with 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 h) in control subjects compared to 123 ± 102k (12.3 h) in ALS with 'adaptive' (24:2.4:1.6) Nf stoichiometry (not significant) and increased significantly to 355 ± 330k (35.5 h) with 'luxury' (7:3:2) Nf subunit stoichiometry (p < 0.0001 for each comparison). Longitudinal disease progression-related energy consumption was highest with a 'luxury' (7:3:2) 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. © 2018 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

Citation

Elisabetta Zucchi, Ching-Hua Lu, Yunju Cho, Rakwoo Chang, Rocco Adiutori, Irene Zubiri, Mauro Ceroni, Cristina Cereda, Orietta Pansarasa, Linda Greensmith, Andrea Malaspina, Axel Petzold. A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry. Journal of neurochemistry. 2018 Sep;146(5):631-641