title: Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS.
abstract: Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. This interaction is found on isolated spinal cord mitochondria and can be reconstituted with purified components in vitro. ADP passage through the outer membrane is diminished in spinal mitochondria from mutant SOD1-expressing ALS rats. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of individual channels when reconstituted in a lipid bilayer. Reduction of VDAC1 activity with targeted gene disruption is shown to diminish survival by accelerating onset of fatal paralysis in mice expressing the ALS-causing mutation SOD1(G37R). Taken together, our results establish a direct link between misfolded mutant SOD1 and mitochondrial dysfunction in this form of inherited ALS.
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Israelson
authors.forename: Nir
authors.initials: N
authors.lastname: Arbel
authors.forename: Sandrine
authors.initials: S
authors.lastname: Da Cruz
authors.forename: Hristelina
authors.initials: H
authors.lastname: Ilieva
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Varda
authors.initials: V
authors.lastname: Shoshan-Barmatz
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004553:Electric Conductivity; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism; D020125:Mutation, Missense; D010243:Paralysis / Q000378:metabolism / Q000401:mortality; D017510:Protein Folding; D051381:Rats; D055647:Rats, Transgenic; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; C000606290:SOD1 protein, human; C494763:Vdac1 protein, mouse; D000244:Adenosine Diphosphate; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D050995:Voltage-Dependent Anion Channel 1; D002118:Calcium
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