β-Methylamino-L-alanine substitution of serine in SOD1 suggests a direct role in ALS etiology

Research output: Contribution to journalArticle

Abstract

Exposure to the environmental toxin β-methylamino-L-alanine (BMAA) is linked to amyotrophic lateral sclerosis (ALS), but its disease-promoting mechanism remains unknown. We propose that incorporation of BMAA into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1) upon translation promotes protein misfolding and aggregation, which has been linked to ALS onset and progression. Using molecular simulation and predictive energetic computation, we demonstrate that substituting any serine with BMAA in SOD1 results in structural destabilization and aberrant dynamics, promoting neurotoxic SOD1 aggregation. We propose that translational incorporation of BMAA into SOD1 is directly responsible for its toxicity in neurodegeneration, and BMAA modification of SOD1 may serve as a biomarker of ALS.

Original languageEnglish (US)
Article numbere1007225
JournalPLoS computational biology
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

etiology
Amyotrophic Lateral Sclerosis
Alanine
alanine
serine
Serine
Substitution
Lateral
substitution
Substitution reactions
Agglomeration
Proteins
protein
Biomarkers
toxin
Toxicity
biomarker
Aggregation
energetics
toxicity

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Cite this

@article{3e305451768c40f1bff715717e5a522f,
title = "β-Methylamino-L-alanine substitution of serine in SOD1 suggests a direct role in ALS etiology",
abstract = "Exposure to the environmental toxin β-methylamino-L-alanine (BMAA) is linked to amyotrophic lateral sclerosis (ALS), but its disease-promoting mechanism remains unknown. We propose that incorporation of BMAA into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1) upon translation promotes protein misfolding and aggregation, which has been linked to ALS onset and progression. Using molecular simulation and predictive energetic computation, we demonstrate that substituting any serine with BMAA in SOD1 results in structural destabilization and aberrant dynamics, promoting neurotoxic SOD1 aggregation. We propose that translational incorporation of BMAA into SOD1 is directly responsible for its toxicity in neurodegeneration, and BMAA modification of SOD1 may serve as a biomarker of ALS.",
author = "Proctor, {Elizabeth Anne} and Mowrey, {David D.} and Nikolay Dokholyan",
year = "2019",
month = "7",
day = "1",
doi = "10.1371/journal.pcbi.1007225",
language = "English (US)",
volume = "15",
journal = "PLoS Computational Biology",
issn = "1553-734X",
publisher = "Public Library of Science",
number = "7",

}

β-Methylamino-L-alanine substitution of serine in SOD1 suggests a direct role in ALS etiology. / Proctor, Elizabeth Anne; Mowrey, David D.; Dokholyan, Nikolay.

In: PLoS computational biology, Vol. 15, No. 7, e1007225, 01.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - β-Methylamino-L-alanine substitution of serine in SOD1 suggests a direct role in ALS etiology

AU - Proctor, Elizabeth Anne

AU - Mowrey, David D.

AU - Dokholyan, Nikolay

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Exposure to the environmental toxin β-methylamino-L-alanine (BMAA) is linked to amyotrophic lateral sclerosis (ALS), but its disease-promoting mechanism remains unknown. We propose that incorporation of BMAA into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1) upon translation promotes protein misfolding and aggregation, which has been linked to ALS onset and progression. Using molecular simulation and predictive energetic computation, we demonstrate that substituting any serine with BMAA in SOD1 results in structural destabilization and aberrant dynamics, promoting neurotoxic SOD1 aggregation. We propose that translational incorporation of BMAA into SOD1 is directly responsible for its toxicity in neurodegeneration, and BMAA modification of SOD1 may serve as a biomarker of ALS.

AB - Exposure to the environmental toxin β-methylamino-L-alanine (BMAA) is linked to amyotrophic lateral sclerosis (ALS), but its disease-promoting mechanism remains unknown. We propose that incorporation of BMAA into the ALS-linked protein Cu,Zn superoxide dismutase (SOD1) upon translation promotes protein misfolding and aggregation, which has been linked to ALS onset and progression. Using molecular simulation and predictive energetic computation, we demonstrate that substituting any serine with BMAA in SOD1 results in structural destabilization and aberrant dynamics, promoting neurotoxic SOD1 aggregation. We propose that translational incorporation of BMAA into SOD1 is directly responsible for its toxicity in neurodegeneration, and BMAA modification of SOD1 may serve as a biomarker of ALS.

UR - http://www.scopus.com/inward/record.url?scp=85070851709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070851709&partnerID=8YFLogxK

U2 - 10.1371/journal.pcbi.1007225

DO - 10.1371/journal.pcbi.1007225

M3 - Article

C2 - 31323035

AN - SCOPUS:85070851709

VL - 15

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-734X

IS - 7

M1 - e1007225

ER -