title: Misfolded SOD1 is not a primary component of sporadic ALS.
abstract: A common feature of inherited and sporadic ALS is accumulation of abnormal proteinaceous inclusions in motor neurons and glia. SOD1 is the major protein component accumulating in patients with SOD1 mutations, as well as in mutant SOD1 mouse models. ALS-linked mutations of SOD1 have been shown to increase its propensity to misfold and/or aggregate. Antibodies specific for monomeric or misfolded SOD1 have detected misfolded SOD1 accumulating predominantly in spinal cord motor neurons of ALS patients with SOD1 mutations. We now use seven different conformationally sensitive antibodies to misfolded human SOD1 (including novel high affinity antibodies currently in pre-clinical development) coupled with immunohistochemistry, immunofluorescence and immunoprecipitation to test for the presence of misfolded SOD1 in high quality human autopsy samples. Whereas misfolded SOD1 is readily detectable in samples from patients with SOD1 mutations, it is below detection limits for all of our measures in spinal cord and cortex tissues from patients with sporadic or non-SOD1 inherited ALS. The absence of evidence for accumulated misfolded SOD1 supports a conclusion that SOD1 misfolding is not a primary component of sporadic ALS.
authors.affiliation: Laboratory for Cell Biology, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Da Cruz
authors.affiliation: Laboratory for Cell Biology, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Anh
authors.initials: A
authors.lastname: Bui
authors.affiliation: Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA.
authors.forename: Shahram
authors.initials: S
authors.lastname: Saberi
authors.affiliation: Laboratory for Cell Biology, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stauffer
authors.affiliation: Laboratory for Cell Biology, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis-Downes
authors.affiliation: Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Schulte
authors.affiliation: Department of Pathology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Pizzo
authors.affiliation: Laboratory for Cell Biology, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.|Fate Therapeutics, 3535 General Atomics Court, San Diego, CA, 92121, USA.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Parone
authors.affiliation: Laboratory for Cell Biology, Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA. dcleveland@ucsd.edu.|Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. dcleveland@ucsd.edu.|Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. dcleveland@ucsd.edu.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. jravits@ucsd.edu.
authors.forename: John
authors.initials: J
authors.lastname: Ravits
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D017510:Protein Folding; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis (ALS); Human patients; Misfolding; Neurodegeneration; Neuropathology; Sporadic (SALS); Superoxide dismutase (SOD1)