title: Distinct conformers of transmissible misfolded SOD1 distinguish human SOD1-FALS from other forms of familial and sporadic ALS.
abstract: Evidence of misfolded wild-type superoxide dismutase 1 (SOD1) has been detected in spinal cords of sporadic ALS (sALS) patients, suggesting an etiological relationship to SOD1-associated familial ALS (fALS). Given that there are currently a number of promising therapies under development that target SOD1, it is of critical importance to better understand the role of misfolded SOD1 in sALS. We previously demonstrated the permissiveness of the G85R-SOD1:YFP mouse model for MND induction following injection with tissue homogenates from paralyzed transgenic mice expressing SOD1 mutations. This prompted us to examine whether WT SOD1 can self-propagate misfolding of the G85R-SOD1:YFP protein akin to what has been observed with mutant SOD1. Using the G85R-SOD1:YFP mice, we demonstrate that misfolded conformers of recombinant WT SOD1, produced in vitro, induce MND with a distinct inclusion pathology. Furthermore, the distinct pathology remains upon successive passages in the G85R-SOD1:YFP mice, strongly supporting the notion for conformation-dependent templated propagation and SOD1 strains. To determine the presence of a similar misfolded WT SOD1 conformer in sALS tissue, we screened homogenates from patients diagnosed with sALS, fALS, and non-ALS disease in an organotypic spinal cord slice culture assay. Slice cultures from G85R-SOD1:YFP mice exposed to spinal homogenates from patients diagnosed with ALS caused by the A4V mutation in SOD1 developed robust inclusion pathology, whereas spinal homogenates from more than 30 sALS cases and various controls failed. These findings suggest that mutant SOD1 has prion-like attributes that do not extend to SOD1 in sALS tissues.
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA. jayers.123ja@ufl.edu.
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Ayers
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Diamond
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sari
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Fromholt
authors.affiliation: Department of Biological Sciences, St. Mary's University, San Antonio, TX, 78228, USA.|Department of Biochemistry and X-ray Crystallography Core Laboratory, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Galaleldeen
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Lyle W
authors.initials: LW
authors.lastname: Ostrow
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.affiliation: Department of Biological Sciences, St. Mary's University, San Antonio, TX, 78228, USA.|Department of Veterans Affairs, Geriatric Research, Education, and Clinical Center, South Texas Health Care System, San Antonio, TX, 78229, USA.
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA.|SantaFe HealthCare Alzheimer's Disease Research Center, McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D009924:Organ Culture Techniques; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000175:diagnosis / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000072105:Superoxide Dismutase-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000682:Amyloid; D001426:Bacterial Proteins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Prion; Strains; Superoxide dismutase-1; fALS; sALS