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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Neurochemistry
DOIs
Publication statusE-pub ahead of print - Jun 30 2018

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Amyotrophic Lateral Sclerosis
Motor Neurons
Stoichiometry
Neurons
Disease Progression
Proteins
Neurofilament Proteins
Brushes
Intermediate Filaments
Protein Isoforms
Adenosine Triphosphate
Biomarkers
Light
Costs and Cost Analysis
Energy utilization
Costs

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A motor neuron strategy to save time and energy in neurodegeneration : adaptive protein stoichiometry. / Zucchi, Elisabetta; Lu, Ching-Hua; Cho, Yunju; Chang, Rakwoo; Adiutori, Rocco; Zubiri, Irene; Ceroni, Mauro; Cereda, Cristina; Pansarasa, Orietta; Greensmith, Linda; Malaspina, Andrea; Petzold, Axel.

In: Journal of Neurochemistry, 30.06.2018.

Research output: Contribution to journalArticle

Zucchi, Elisabetta ; Lu, Ching-Hua ; Cho, Yunju ; Chang, Rakwoo ; Adiutori, Rocco ; Zubiri, Irene ; Ceroni, Mauro ; Cereda, Cristina ; Pansarasa, Orietta ; Greensmith, Linda ; Malaspina, Andrea ; Petzold, Axel. / A motor neuron strategy to save time and energy in neurodegeneration : adaptive protein stoichiometry. In: Journal of Neurochemistry. 2018.
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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.",
author = "Elisabetta Zucchi and Ching-Hua Lu and Yunju Cho and Rakwoo Chang and Rocco Adiutori and Irene Zubiri and Mauro Ceroni and Cristina Cereda and Orietta Pansarasa and Linda Greensmith and Andrea Malaspina and Axel Petzold",
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T1 - A motor neuron strategy to save time and energy in neurodegeneration

T2 - adaptive protein stoichiometry

AU - Zucchi, Elisabetta

AU - Lu, Ching-Hua

AU - Cho, Yunju

AU - Chang, Rakwoo

AU - Adiutori, Rocco

AU - Zubiri, Irene

AU - Ceroni, Mauro

AU - Cereda, Cristina

AU - Pansarasa, Orietta

AU - Greensmith, Linda

AU - Malaspina, Andrea

AU - Petzold, Axel

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/6/30

Y1 - 2018/6/30

N2 - 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.

AB - 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.

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DO - 10.1111/jnc.14542

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JF - Journal of Neurochemistry

SN - 0022-3042

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