title: Gibbs Energy of Superoxide Dismutase Heterodimerization Accounts for Variable Survival in Amyotrophic Lateral Sclerosis.
abstract: The exchange of subunits between homodimeric mutant Cu, Zn superoxide dismutase (SOD1) and wild-type (WT) SOD1 is suspected to be a crucial step in the onset and progression of amyotrophic lateral sclerosis (ALS). The rate, mechanism, and ΔG of heterodimerization (ΔGHet) all remain undetermined, due to analytical challenges in measuring heterodimerization. This study used capillary zone electrophoresis to measure rates of heterodimerization and ΔGHet for seven ALS-variant apo-SOD1 proteins that are clinically diverse, producing mean survival times between 2 and 12 years (postdiagnosis). The ΔGHet of each ALS variant SOD1 correlated with patient survival time after diagnosis (R(2) = 0.98), with more favorable ΔGHet correlating with shorter survival by 4.8 years per kJ. Rates of heterodimerization did not correlate with survival time or age of disease onset. Metalation diminished the rate of subunit exchange by up to ∼38-fold but only altered ΔGHet by <1 kJ mol(-1). Medicinal targeting of heterodimer thermodynamics represents a plausible strategy for prolonging life in SOD1-linked ALS.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76798-7348, United States.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76798-7348, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Acerson
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76798-7348, United States.
authors.forename: Alireza
authors.initials: A
authors.lastname: Abdolvahabi
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76798-7348, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mowery
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76798-7348, United States.
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Shaw
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000401:mortality*; D002152:Calorimetry, Differential Scanning; D019075:Electrophoresis, Capillary / Q000379:methods; D004795:Enzyme Stability; D006207:Half-Life; D006801:Humans; D009154:Mutation; D055503:Protein Multimerization; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1