Parsing disease‐relevant protein modifications from epiphenomena: perspective on the structural basis of SOD1‐mediated ALS
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Conformational change and modification of proteins are involved in many cellular functions. However, they can also have adverse effects that are implicated in numerous diseases. How structural change promotes disease is generally not well‐understood. This perspective illustrates how mass spectrometry (MS), followed by toxicological and epidemiological validation, can discover disease‐relevant structural changes and therapeutic strategies. We (with our collaborators) set out to characterize the structural and toxic consequences of disease‐associated mutations and post‐translational modifications (PTMs) of the cytosolic antioxidant protein Cu/Zn‐superoxide dismutase (SOD1). Previous genetic studies discovered >180 different mutations in the SOD1 gene that caused familial (inherited) amyotrophic lateral sclerosis (fALS). Using hydrogen–deuterium exchange with mass spectrometry, we determined that diverse disease‐associated SOD1 mutations cause a common structural defect – perturbation of the SOD1 electrostatic loop. X‐ray crystallographic studies had demonstrated that this leads to protein aggregation through a specific interaction between the electrostatic loop and an exposed beta‐barrel edge strand. Using epidemiology methods, we then determined that decreased SOD1 stability and increased protein aggregation are powerful risk factors for fALS progression, with a combined hazard ratio > 300 (for comparison, a lifetime of smoking is associated with a hazard ratio of ~15 for lung cancer). The resulting structural model of fALS etiology supported the hypothesis that some sporadic ALS (sALS, ~80% of ALS is not associated with a gene defect) could be caused by post‐translational protein modification of wild‐type SOD1. We developed immunocapture antibodies and high sensitivity top‐down MS methods and characterized PTMs of wild‐type SOD1 using human tissue samples. Using global hydrogen–deuterium exchange, X‐ray crystallography and neurotoxicology, we then characterized toxic and protective subsets of SOD1 PTMs. To cap this perspective, we present proof‐of‐concept that post‐translational modification can cause disease. We show that numerous mutations (N➔D; Q➔E), which result in the same chemical structure as the PTM deamidation, cause multiple diseases. Copyright © 2017 John Wiley & Sons, Ltd.
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In neurological disease and aging, modified proteins are the histopathological hallmarks of a number of diseases, such as SOD1 in amyotrophic lateral sclerosis (ALS), and a class of diseases long referred to as the proteinopathies, including tauopathies in Alzheimer's disease and inclusions of amyloid beta, alpha-synuclein in Parkinson's and multiple secondary ubiquitinopathies.
“In neurological disease and aging, modified proteins are the histopathological hallmarks of a number of diseases, such as SOD1 in amyotrophic lateral sclerosis (ALS) 56,57 , and a class of diseases long referred to as the proteinopathies 57 , including tauopathies in Alzheimer's disease 58 and inclusions of amyloidβ 59 , α -synuclein in Parkinson's 60,61 and multiple secondary ubiquitinopathies”
From How many human proteoforms are there? (2018) · cites this paper as [57]
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How many human proteoforms are there?
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- Authors
- Schmitt, N. D., & Agar, J. N.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Agar, J. N.
- Venue
- Journal of Mass Spectrometry
- Publisher
- Wiley
- Published
- 2017-07
- Volume
- 52
- Issue
- 7
- Pages
- 480-491
- ISSN
- 1076-5174 (ISSN-L)
- 1096-9888
- PMC
- PMC6002871
- OpenAlex
- W2734586273
- Cited by
- 29
- References
- 115
- Citations by year
- 2026: 2 · 2024: 6 · 2022: 1 · 2021: 3 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 2
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Mass Spectrometry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1R21NS071256, R01NS065263)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- amyotrophic lateral sclerosis, SOD1, post-translational modification, deamidation, protein aggregation, hydrogen-deuterium exchange, familial ALS, sporadic ALS, protein stability, top-down mass spectrometry, neurotoxicity, disease risk factors
- MeSH terms
- Superoxide Dismutase-1, Proof of Concept Study, Amyotrophic Lateral Sclerosis, Binding Sites, Computer Simulation, Epidemiologic Methods, Humans, Models, Molecular, Mutation, Protein Binding, Protein Conformation, Protein Processing, Post-Translational, Mass Spectrometry, Crystallography, X-Ray, Static Electricity, Proteolysis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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