Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Munishikha Kalia, Mattia Miotto, Deborah Ness, Sarah Opie-Martin, Thomas P. Spargo, Lorenzo Di Rienzo, Tommaso Biagini, Francesco Petrizzelli, Ahmad Al Khleifat, Renata Kabiljo, Project MinE ALS Sequencing Consortium, SOD1-ALS clinical and genetic data collection group, Tommaso Mazza, Giancarlo Ruocco, Edoardo Milanetti, Richard JB Dobson, Ammar Al-Chalabi, Alfredo Iacoangeli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, ‘wild-type like’ (WTL) and ‘metal binding region’ (MBR) variants, based on their structural location and biophysical properties. MBR variants, but not WTL variants, were associated with a reduction of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants, we showed that the survival time of patients carrying an MBR variant is generally longer (∼6 years median difference, p < 0.001) with respect to patients with a WTL variant. In conclusion, our study highlighted key differences in the dynamic behaviour between WTL and MBR SOD1 variants, and between variants and wild-type SOD1 at an atomic and molecular level, that could be further investigated to explain the associated phenotypic variability. Our results support the hypothesis of a decoupling between mechanisms of onset and progression of SOD1 ALS, and an involvement of loss-of-function of SOD1 with the disease progression.

Original languageEnglish
Pages (from-to)5296-5308
Number of pages13
JournalComputational and Structural Biotechnology Journal
Volume21
Early online date17 Sept 2023
DOIs
Publication statusPublished - 2023

Keywords

  • Amyotrophic lateral sclerosis
  • Diseaseassociated SOD1 mutations
  • Molecular dynamics (MD) simulations
  • Performed principal component analysis
  • Superoxide Dismutase type 1 (SOD1)
  • Survival analysis

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