Misfolded SOD1 is not a primary component of sporadic ALS

• Published in: Acta neuropathologica Vol. 134; no. 1; pp. 97 - 111
• Main Authors: Da Cruz, Sandrine, Bui, Anh, Saberi, Shahram, Lee, Sandra K., Stauffer, Jennifer, McAlonis-Downes, Melissa, Schulte, Derek, Pizzo, Donald P., Parone, Philippe A., Cleveland, Don W., Ravits, John
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2017; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animal models; Animals; Antibodies; Autopsy; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Disease Models, Animal; Female; Humans; Immunofluorescence; Immunoglobulins; Immunohistochemistry; Immunoprecipitation; Male; Medicine; Medicine & Public Health; Mice, Transgenic; Middle Aged; Motor neurons; Motor task performance; Mutation; Neuronal-glial interactions; Neurosciences; Original Paper; Pathology; Protein Folding; Spinal cord; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide dismutase; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Young Adult; Sporadic (SALS); Human patients; Amyotrophic lateral sclerosis (ALS); Neurodegeneration; Neuropathology; Superoxide dismutase (SOD1); Misfolding
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-017-1688-8

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.