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

By D. A. Bosco, G. Morfini, N. M. Karabacak, Yuyu Song, F. Gros-Louis, P. Pasinelli, H. Goolsby, B. Fontaine, Nathan Lemay, D. McKenna-Yasek and 5 more. Nature Neuroscience, 2010

712 citations recorded by the source corpus.

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.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/4f65cc95ff32f87bd68ba37e6b60da52d1cf2ce6

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In Genetics

1. Beth Levine
2. C. López‐Otín
3. P. Bonaldo
4. D. Klionsky
5. G. Hotamisligil
6. S. Bultman
7. R. Shaw
8. M. Felici

In Neurology

1. D. Klionsky
2. D. Rubinsztein
3. Beth Levine
4. Sovan Sarkar
5. Katherine R Parzych
6. Edward A. Fon
7. T. Johansen
8. Eric H. Baehrecke

Citations in the corpus

• Guidelines for the use and interpretation of assays for monitoring autophagy (2012, background): “In addition, the wild-type SOD1 protein can be oxidized, and this form (SODox) is associated with sporadic cases of amyotrophic lateral sclerosis.(106) Thus, the oxidized form of SOD1 might interfere with autophagy, and, if so, it may not be a good choice for a marker to monitor steady-state autopha”