Gibbs Energy of Superoxide Dismutase Heterodimerization Accounts for Variable Survival in Amyotrophic Lateral Sclerosis

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• 作者：Yunhua Shi ; Mark J. Acerson ; Alireza Abdolvahabi ; Richard A. Mowery ; Bryan F. Shaw
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：April 27, 2016
• 年：2016
• 卷：138
• 期：16
• 页码：5351-5362
• 全文大小：983K
• 年卷期：0
• ISSN：1520-5126

文摘

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 (ΔG_Het) all remain undetermined, due to analytical challenges in measuring heterodimerization. This study used capillary zone electrophoresis to measure rates of heterodimerization and ΔG_Het for seven ALS-variant apo-SOD1 proteins that are clinically diverse, producing mean survival times between 2 and 12 years (postdiagnosis). The ΔG_Het of each ALS variant SOD1 correlated with patient survival time after diagnosis (R² = 0.98), with more favorable ΔG_Het 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 ΔG_Het by <1 kJ mol^–1. Medicinal targeting of heterodimer thermodynamics represents a plausible strategy for prolonging life in SOD1-linked ALS.