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Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS

Daryl A Bosco1, Gerardo Morfini, N Murat Karabacak

  • 1Department of Neurology, University of Massachusetts Medical Center, Worcester, Massachusetts, USA. daryl.bosco@umassmed.edu

Nature Neuroscience
|October 19, 2010
PubMed

Insights

Oxidized wild-type SOD1, like mutant forms, can harm motor neurons and contribute to sporadic ALS. This study reveals a shared toxic mechanism involving misfolded SOD1 in both familial and sporadic forms of the disease.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Mutations in copper/zinc superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (FALS) by conferring toxic functions that impair motor neuron viability.
  • Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons.

Purpose of the Study:

  • To investigate whether wild-type SOD1 can adopt toxic conformations and contribute to sporadic ALS (SALS).
  • To identify common pathogenic mechanisms between FALS and SALS involving SOD1.

Main Methods:

  • Utilized a conformation-specific antibody (C4F6) to detect misfolded SOD1.
  • Examined SOD1 immunoreactivity in motor neurons from SALS patients.
  • Assessed the effect of recombinant and immunopurified oxidized wild-type SOD1 on kinesin-based fast axonal transport.

Main Results:

  • Oxidized wild-type SOD1 and mutant SOD1 share a common conformational epitope recognized by the C4F6 antibody.
  • Misfolded SOD1 species were detected in motor neurons of a subset of SALS patients.
  • Oxidized wild-type SOD1 inhibited fast axonal transport similarly to FALS-linked mutant SOD1.

Conclusions:

  • Wild-type SOD1 can become pathogenic in SALS by adopting misfolded conformations.
  • An SOD1-dependent pathogenic mechanism, involving impaired axonal transport, is common to both FALS and SALS.
  • These findings suggest a unified view of SOD1-mediated motor neuron degeneration in ALS.

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