Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS.
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.
Bosco
Daryl A
DA
Department of Neurology, University of Massachusetts Medical Center, Worcester, Massachusetts, USA. daryl.bosco@umassmed.edu
Morfini
Gerardo
G
Karabacak
N Murat
NM
Song
Yuyu
Y
Gros-Louis
Francois
F
Pasinelli
Piera
P
Goolsby
Holly
H
Fontaine
Benjamin A
BA
Lemay
Nathan
N
McKenna-Yasek
Diane
D
Frosch
Matthew P
MP
Agar
Jeffrey N
JN
Julien
Jean-Pierre
JP
Brady
Scott T
ST
Brown
Robert H
RH
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000888:Antibodies, Anti-Idiotypic; D018360:Crystallography, X-Ray / Q000379:methods; D018604:Epitope Mapping / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics* / Q000276:immunology; D010084:Oxidation-Reduction; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000150:complications* / Q000235:genetics / Q000473:pathology; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D000072105:Superoxide Dismutase-1
D000888:Antibodies, Anti-Idiotypic; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1