Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice

Barry Gertz, Margaret Wong, Lee J Martin

Research output: Contribution to journalArticle

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that causes degeneration of motor neurons and paralysis. Approximately 20% of familial ALS cases have been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene, but it is unclear how mutations in the protein result in motor neuron degeneration. Transgenic (tg) mice expressing mutated forms of human SOD1 (hSOD1) develop clinical and pathological features similar to those of ALS. We used tg mice expressing hSOD1-G93A, hSOD1-G37R, and hSOD1-wild-type to investigate a new subcellular pathology involving mutant hSOD1 protein prominently localizing to the nuclear compartment and disruption of the architecture of nuclear gems. We developed methods for extracting relatively pure cell nucleus fractions from mouse CNS tissues and demonstrate a low nuclear presence of endogenous SOD1 in mouse brain and spinal cord, but prominent nuclear accumulation of hSOD1-G93A,-G37R, and-wild-type in tg mice. The hSOD1 concentrated in the nuclei of spinal cord cells, particularly motor neurons, at a young age. The survival motor neuron protein (SMN) complex is disrupted in motor neuron nuclei before disease onset in hSOD1-G93A and-G37R mice; age-matched hSOD1-wild-type mice did not show SMN disruption despite a nuclear presence. Our data suggest new mechanisms involving hSOD1 accumulation in the cell nucleus and mutant hSOD1-specific perturbations in SMN localization with disruption of the nuclear SMN complex in ALS mice and suggest an overlap of pathogenic mechanisms with spinal muscular atrophy.

Original languageEnglish (US)
Pages (from-to)162-177
Number of pages16
JournalJournal of Neuropathology and Experimental Neurology
Volume71
Issue number2
DOIs
StatePublished - Feb 2012

Fingerprint

SMN Complex Proteins
Amyotrophic Lateral Sclerosis
Motor Neurons
Transgenic Mice
Cell Nucleus
Spinal Cord
Spinal Muscular Atrophy
Nerve Degeneration
Mutation
Proteins
Survival
Paralysis
Neurodegenerative Diseases
Superoxide Dismutase

Keywords

  • Cajal body
  • Gemin 1
  • Nuclear gems
  • Snurportin
  • Spinal muscular atrophy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

@article{9c09c35c077e4cb599bfa989c3b27564,
title = "Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice",
abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that causes degeneration of motor neurons and paralysis. Approximately 20{\%} of familial ALS cases have been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene, but it is unclear how mutations in the protein result in motor neuron degeneration. Transgenic (tg) mice expressing mutated forms of human SOD1 (hSOD1) develop clinical and pathological features similar to those of ALS. We used tg mice expressing hSOD1-G93A, hSOD1-G37R, and hSOD1-wild-type to investigate a new subcellular pathology involving mutant hSOD1 protein prominently localizing to the nuclear compartment and disruption of the architecture of nuclear gems. We developed methods for extracting relatively pure cell nucleus fractions from mouse CNS tissues and demonstrate a low nuclear presence of endogenous SOD1 in mouse brain and spinal cord, but prominent nuclear accumulation of hSOD1-G93A,-G37R, and-wild-type in tg mice. The hSOD1 concentrated in the nuclei of spinal cord cells, particularly motor neurons, at a young age. The survival motor neuron protein (SMN) complex is disrupted in motor neuron nuclei before disease onset in hSOD1-G93A and-G37R mice; age-matched hSOD1-wild-type mice did not show SMN disruption despite a nuclear presence. Our data suggest new mechanisms involving hSOD1 accumulation in the cell nucleus and mutant hSOD1-specific perturbations in SMN localization with disruption of the nuclear SMN complex in ALS mice and suggest an overlap of pathogenic mechanisms with spinal muscular atrophy.",
keywords = "Cajal body, Gemin 1, Nuclear gems, Snurportin, Spinal muscular atrophy",
author = "Barry Gertz and Margaret Wong and Martin, {Lee J}",
year = "2012",
month = "2",
doi = "10.1097/NEN.0b013e318244b635",
language = "English (US)",
volume = "71",
pages = "162--177",
journal = "American Journal of Psychotherapy",
issn = "0002-9564",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice

AU - Gertz, Barry

AU - Wong, Margaret

AU - Martin, Lee J

PY - 2012/2

Y1 - 2012/2

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that causes degeneration of motor neurons and paralysis. Approximately 20% of familial ALS cases have been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene, but it is unclear how mutations in the protein result in motor neuron degeneration. Transgenic (tg) mice expressing mutated forms of human SOD1 (hSOD1) develop clinical and pathological features similar to those of ALS. We used tg mice expressing hSOD1-G93A, hSOD1-G37R, and hSOD1-wild-type to investigate a new subcellular pathology involving mutant hSOD1 protein prominently localizing to the nuclear compartment and disruption of the architecture of nuclear gems. We developed methods for extracting relatively pure cell nucleus fractions from mouse CNS tissues and demonstrate a low nuclear presence of endogenous SOD1 in mouse brain and spinal cord, but prominent nuclear accumulation of hSOD1-G93A,-G37R, and-wild-type in tg mice. The hSOD1 concentrated in the nuclei of spinal cord cells, particularly motor neurons, at a young age. The survival motor neuron protein (SMN) complex is disrupted in motor neuron nuclei before disease onset in hSOD1-G93A and-G37R mice; age-matched hSOD1-wild-type mice did not show SMN disruption despite a nuclear presence. Our data suggest new mechanisms involving hSOD1 accumulation in the cell nucleus and mutant hSOD1-specific perturbations in SMN localization with disruption of the nuclear SMN complex in ALS mice and suggest an overlap of pathogenic mechanisms with spinal muscular atrophy.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that causes degeneration of motor neurons and paralysis. Approximately 20% of familial ALS cases have been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene, but it is unclear how mutations in the protein result in motor neuron degeneration. Transgenic (tg) mice expressing mutated forms of human SOD1 (hSOD1) develop clinical and pathological features similar to those of ALS. We used tg mice expressing hSOD1-G93A, hSOD1-G37R, and hSOD1-wild-type to investigate a new subcellular pathology involving mutant hSOD1 protein prominently localizing to the nuclear compartment and disruption of the architecture of nuclear gems. We developed methods for extracting relatively pure cell nucleus fractions from mouse CNS tissues and demonstrate a low nuclear presence of endogenous SOD1 in mouse brain and spinal cord, but prominent nuclear accumulation of hSOD1-G93A,-G37R, and-wild-type in tg mice. The hSOD1 concentrated in the nuclei of spinal cord cells, particularly motor neurons, at a young age. The survival motor neuron protein (SMN) complex is disrupted in motor neuron nuclei before disease onset in hSOD1-G93A and-G37R mice; age-matched hSOD1-wild-type mice did not show SMN disruption despite a nuclear presence. Our data suggest new mechanisms involving hSOD1 accumulation in the cell nucleus and mutant hSOD1-specific perturbations in SMN localization with disruption of the nuclear SMN complex in ALS mice and suggest an overlap of pathogenic mechanisms with spinal muscular atrophy.

KW - Cajal body

KW - Gemin 1

KW - Nuclear gems

KW - Snurportin

KW - Spinal muscular atrophy

UR - http://www.scopus.com/inward/record.url?scp=84856051539&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856051539&partnerID=8YFLogxK

U2 - 10.1097/NEN.0b013e318244b635

DO - 10.1097/NEN.0b013e318244b635

M3 - Article

C2 - 22249462

AN - SCOPUS:84856051539

VL - 71

SP - 162

EP - 177

JO - American Journal of Psychotherapy

JF - American Journal of Psychotherapy

SN - 0002-9564

IS - 2

ER -