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Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
Free energy calculations of ALS-causing SOD1 mutants reveal common perturbations to stability and dynamics along the
Nicholas G M Wells1, Grant A Tillinghast1,2, Alison L O'Neil1
1Department of Chemistry, Wesleyan University, Middletown, Connecticut, USA.
Abstract:
With over 150 heritable mutations identified as disease-causative, superoxide dismutase 1 (SOD1) has been a main target of amyotrophic lateral sclerosis (ALS) research and therapeutic efforts. However, recent evidence has suggested that neither loss of function nor protein aggregation is responsible for promoting neurotoxicity. Furthermore, there is no clear pattern to the nature or the location of these mutations that could suggest a molecular mechanism behind SOD1-linked ALS. Here, we utilize reliable and accurate computational techniques to predict the perturbations of 10 such mutations to the free energy changes of SOD1 as it matures from apo monomer to metallated dimer. We find that the free energy perturbations caused by these mutations strongly depend on maturational progress, indicating the need for state-specific therapeutic targeting. We also find that many mutations exhibit similar patterns of perturbation to native and non-native maturation, indicating strong thermodynamic coupling between the dynamics at various sites of maturation within SOD1. These results suggest the presence of an allosteric network in SOD1 which is vulnerable to disruption by these mutations. Analysis of these perturbations may contribute to uncovering a unifying molecular mechanism which explains SOD1-linked ALS and help to guide future therapeutic efforts.
Insights
Computational analysis reveals that mutations in superoxide dismutase 1 (SOD1) disrupt its maturation process. These findings highlight the need for state-specific therapies targeting amyotrophic lateral sclerosis (ALS).
Area of Science:
- Biochemistry
- Neuroscience
- Computational Biology
Background:
- Over 150 mutations in superoxide dismutase 1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS).
- Current research questions whether loss-of-function or aggregation drives neurotoxicity in SOD1-linked ALS.
- The molecular mechanisms underlying SOD1 mutations in ALS remain unclear.
Purpose of the Study:
- To computationally predict the impact of 10 SOD1 mutations on protein maturation free energy changes.
- To investigate the relationship between mutation type, location, and thermodynamic stability.
- To identify potential unifying molecular mechanisms for SOD1-linked ALS.
Main Methods:
- Utilized computational techniques to predict free energy perturbations.
- Analyzed SOD1 maturation from apo monomer to metallated dimer.
- Examined thermodynamic coupling between different maturation sites.
Main Results:
- Mutation-induced free energy perturbations are dependent on the maturational stage of SOD1.
- Many mutations show similar perturbation patterns across native and non-native maturation pathways.
- Evidence suggests an allosteric network within SOD1 is disrupted by these mutations.
Conclusions:
- SOD1 maturation is sensitive to specific mutations, necessitating state-specific therapeutic strategies for ALS.
- Thermodynamic coupling indicates an interconnected network within SOD1 affected by mutations.
- Understanding these allosteric disruptions may reveal a unifying mechanism for SOD1-linked ALS and guide therapeutic development.
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