Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

Han Xiang Deng, Yong Shi, Yoshiaki Furukawa, Hong Zhai, Ronggen Fu, Erdong Liu, George H. Gorrie, Mohammad S. Khan, Wu Yen Hung, Eileen H. Bigio, Thomas Lukas, Mauro C. Dal Canto, Thomas V. O'Halloran, Teepu Siddique

Research output: Contribution to journalArticle

309 Citations (Scopus)

Abstract

Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.

Original languageEnglish
Pages (from-to)7142-7147
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number18
DOIs
Publication statusPublished - 2006 May 2
Externally publishedYes

Fingerprint

Amyotrophic Lateral Sclerosis
Mitochondria
Transgenic Mice
Poisons
Phenotype
Mitochondrial Proteins
Disulfides
Neurodegenerative Diseases
Detergents
Oxidation-Reduction
Free Radicals
Cysteine
Disease Progression
Spinal Cord
Mutation
Genes
Superoxide Dismutase-1

Keywords

  • Crosslinked
  • Disulfide bonds
  • Neurodegeneration
  • Oxidation
  • Protein aggregation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. / Deng, Han Xiang; Shi, Yong; Furukawa, Yoshiaki; Zhai, Hong; Fu, Ronggen; Liu, Erdong; Gorrie, George H.; Khan, Mohammad S.; Hung, Wu Yen; Bigio, Eileen H.; Lukas, Thomas; Dal Canto, Mauro C.; O'Halloran, Thomas V.; Siddique, Teepu.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 18, 02.05.2006, p. 7142-7147.

Research output: Contribution to journalArticle

Deng, HX, Shi, Y, Furukawa, Y, Zhai, H, Fu, R, Liu, E, Gorrie, GH, Khan, MS, Hung, WY, Bigio, EH, Lukas, T, Dal Canto, MC, O'Halloran, TV & Siddique, T 2006, 'Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 18, pp. 7142-7147. https://doi.org/10.1073/pnas.0602046103
Deng, Han Xiang ; Shi, Yong ; Furukawa, Yoshiaki ; Zhai, Hong ; Fu, Ronggen ; Liu, Erdong ; Gorrie, George H. ; Khan, Mohammad S. ; Hung, Wu Yen ; Bigio, Eileen H. ; Lukas, Thomas ; Dal Canto, Mauro C. ; O'Halloran, Thomas V. ; Siddique, Teepu. / Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 18. pp. 7142-7147.
@article{393e0dd63cac41b9a4849c0887980eeb,
title = "Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria",
abstract = "Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.",
keywords = "Crosslinked, Disulfide bonds, Neurodegeneration, Oxidation, Protein aggregation",
author = "Deng, {Han Xiang} and Yong Shi and Yoshiaki Furukawa and Hong Zhai and Ronggen Fu and Erdong Liu and Gorrie, {George H.} and Khan, {Mohammad S.} and Hung, {Wu Yen} and Bigio, {Eileen H.} and Thomas Lukas and {Dal Canto}, {Mauro C.} and O'Halloran, {Thomas V.} and Teepu Siddique",
year = "2006",
month = "5",
day = "2",
doi = "10.1073/pnas.0602046103",
language = "English",
volume = "103",
pages = "7142--7147",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

AU - Deng, Han Xiang

AU - Shi, Yong

AU - Furukawa, Yoshiaki

AU - Zhai, Hong

AU - Fu, Ronggen

AU - Liu, Erdong

AU - Gorrie, George H.

AU - Khan, Mohammad S.

AU - Hung, Wu Yen

AU - Bigio, Eileen H.

AU - Lukas, Thomas

AU - Dal Canto, Mauro C.

AU - O'Halloran, Thomas V.

AU - Siddique, Teepu

PY - 2006/5/2

Y1 - 2006/5/2

N2 - Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.

AB - Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.

KW - Crosslinked

KW - Disulfide bonds

KW - Neurodegeneration

KW - Oxidation

KW - Protein aggregation

UR - http://www.scopus.com/inward/record.url?scp=33646466296&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646466296&partnerID=8YFLogxK

U2 - 10.1073/pnas.0602046103

DO - 10.1073/pnas.0602046103

M3 - Article

VL - 103

SP - 7142

EP - 7147

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -