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Nat Neurosci. 2010 Nov;13(11):1396-403. doi: 10.1038/nn.2660. Epub 2010 Oct 17.

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

Author information

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

Abstract

Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS.

PMID:
20953194
PMCID:
PMC2967729
DOI:
10.1038/nn.2660
[Indexed for MEDLINE]
Free PMC Article

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