There are ~ 160 mutations in SOD1 (superoxide dismutase-1) that cause amyotrophic lateral sclerosis (ALS), presumably by accelerating SOD1 amyloidogenesis. Like many nucleation processes, SOD1 fibrillization is stochastic (in vitro), which inhibits determination of aggregation rates (and obscures whether rates correlate with patient phenotypes). In this work, we applied Kaplan-Meier method to quantify the probability of apo-SOD1 fibrillization (in vitro) from ~ 1000 replicate amyloid assays of wild-type (WT) SOD1 and nine ALS variants. SOD1 fibrillization was investigated with high-throughput thioflavin-T (ThT) fluorescence assays. We show that Hazard ratios of mutant SOD1 fibrillization (calculated from corresponding Kaplan-Meier plots for each SOD1 mutant) correlated linearly and significantly with Hazard ratios of patient survival in ALS, calculated from ~ 700 clinical data. Thus, Hazard ratios of fibrillization might explain rates of disease progression in patients with ALS. Classical kinetic metrics of fibrillization, i.e., mean lag time and propagation rate, did not correlate as strongly with phenotype as Hazard ratios did. This lack of correlation proves that implementing Kaplan-Meier estimators over classical parameters is very advantageous when dealing with high-throughput protein aggregation kinetic data. We also found a strong correlation between mean ThT fluorescence at lag time, and patient survival (R2 = 0.93); oligomers of SOD1 with weaker fluorescence correlated with shorter survival. This study suggests that SOD1 mutations trigger ALS by altering a property of SOD1 or its oligomers other than the intrinsic rate of amyloid nucleation. Such property might include oligomer stability, rates of intercellular propagation, or affinity for membrane surfaces.

In vitro kinetics of mutant superoxide dismutase-1 aggregation can predict patient survivability in amyotrophic lateral sclerosis

254th National Meeting (2017)

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