title: Kaplan-Meier Meets Chemical Kinetics: Intrinsic Rate of SOD1 Amyloidogenesis Decreased by Subset of ALS Mutations and Cannot Fully Explain Age of Disease Onset.
abstract: Over 150 mutations in SOD1 (superoxide dismutase-1) cause amyotrophic lateral sclerosis (ALS), presumably by accelerating SOD1 amyloidogenesis. Like many nucleation processes, SOD1 fibrillization is stochastic (in vitro), which inhibits the determination of aggregation rates (and obscures whether rates correlate with patient phenotypes). Here, we diverged from classical chemical kinetics and used Kaplan-Meier estimators to quantify the probability of apo-SOD1 fibrillization (in vitro) from ∼103replicate amyloid assays of wild-type (WT) SOD1 and nine ALS variants. The probability of apo-SOD1 fibrillization (expressed as a Hazard ratio) is increased by certain ALS-linked SOD1 mutations but is decreased or remains unchanged by other mutations. Despite this diversity, Hazard ratios of fibrillization correlated linearly with (and for three mutants, approximately equaled) Hazard ratios of patient survival (R2= 0.67; Pearson's r = 0.82). No correlation exists between Hazard ratios of fibrillization and age of initial onset of ALS (R2= 0.09). Thus, Hazard ratios of fibrillization might explain rates of disease progression but not onset. Classical kinetic metrics of fibrillization, i.e., mean lag time and propagation rate, did not correlate as strongly with phenotype (and ALS mutations did not uniformly accelerate mean rate of nucleation or propagation). A strong correlation was found, however, 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 (e.g., oligomer stability; rates of intercellular propagation; affinity for membrane surfaces; and maturation rate).
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Alireza
authors.initials: A
authors.lastname: Abdolvahabi
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.|Institute of Biomedical Studies, Baylor University , Waco, Texas 76706, United States.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Rasouli
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Corbin M
authors.initials: CM
authors.lastname: Croom
authors.affiliation: Department of Chemistry, Rice University , Houston, Texas 77005, United States.
authors.forename: Amir
authors.initials: A
authors.lastname: Aliyan
authors.affiliation: Department of Chemistry, Rice University , Houston, Texas 77005, United States.|Department of Bioengineering, Rice University , Houston, Texas 77005, United States.
authors.forename: Angel A
authors.identifier: 0000-0003-0837-9855
authors.initials: AA
authors.lastname: Martí
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , Waco, Texas 76706, United States.
authors.forename: Bryan F
authors.identifier: 0000-0001-8265-5833
authors.initials: BF
authors.lastname: Shaw
mesh_terms: D017668:Age of Onset; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007700:Kinetics; D009154:Mutation; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1
keywords: Superoxide dismutase; amyotrophic lateral sclerosis; thioflavin-T fluorescence