title: A misfolded dimer of Cu/Zn-superoxide dismutase leading to pathological oligomerization in amyotrophic lateral sclerosis.
abstract: Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) is a pathological hallmark in a familial form of amyotrophic lateral sclerosis. Pathogenic mutations have been proposed to monomerize SOD1 normally adopting a homodimeric configuration and then trigger abnormal oligomerization of SOD1 proteins. Despite this, a misfolded conformation of SOD1 leading to the oligomerization at physiological conditions still remains ambiguous. Here, we show that, around the body temperature (∼37°C), mutant SOD1 maintains a dimeric configuration but lacks most of its secondary structures. Also, such an abnormal SOD1 dimer with significant structural disorder was prone to irreversibly forming the oligomers crosslinked via disulfide bonds. The disulfide-crosslinked oligomers of SOD1 were detected in the spinal cords of the diseased mice expressing mutant SOD1. We hence propose an alternative pathway of mutant SOD1 misfolding that is responsible for oligomerization in the pathologies of the disease.
authors.affiliation: Department of Chemistry, Keio University, Yokohama, 223-8522, Japan.
authors.forename: Itsuki
authors.initials: I
authors.lastname: Anzai
authors.affiliation: Department of Chemistry, Keio University, Yokohama, 223-8522, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tokuda
authors.affiliation: Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, NINS, Okazaki, 444-8585, Japan.|Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8585, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mukaiyama
authors.affiliation: Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, NINS, Okazaki, 444-8585, Japan.|Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8585, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Akiyama
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan.
authors.forename: Fumito
authors.initials: F
authors.lastname: Endo
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo, 105-8512, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.affiliation: Department of Chemistry, Keio University, Yokohama, 223-8522, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017510:Protein Folding; D055503:Protein Multimerization; D000072105:Superoxide Dismutase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004220:Disulfides; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1
keywords: ALS; Cu/Zn-superoxide dismutase; SOD1; amyotrophic lateral sclerosis; circular dichroism spectroscopy; protein misfolding; small-angle X-ray scattering