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

Kalia, Munishikha; Miotto, Mattia; Ness, Deborah; Opie-Martin, Sarah; Spargo, Thomas P.; Di Rienzo, Lorenzo; Biagini, Tommaso; Petrizzelli, Francesco; Al Khleifat, Ahmad; Kabiljo, Renata; Mazza, Tommaso; Ruocco, Giancarlo; Milanetti, Edoardo; Dobson, Richard JB; Al-Chalabi, Ammar; Iacoangeli, Alfredo

doi:10.1016/j.csbj.2023.09.016

Cited by 6 publications

(3 citation statements)

References 63 publications

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“…We only observed an association between singleton carriers and survival period when the C9orf72 repeat expansion was included in the analysis, which may be explained by the C9orf72 pathogenic repeat expansion being associated with a decreased survival period individually 43,44 . Overall, consistent with recent reports 11, 45,46 , these results suggest the genetic architecture underlying ALS risk is decoupled from that underlying survival. Moreover, considering that every modification of risk is expected to correspond to an effect on age of onset 16,47 , our results suggest that this relationship might only explain a limited proportion of the age of onset variability in ALS and the presence of concurring independent mechanisms with large effect is possible.…”

Section: Discussionsupporting

confidence: 91%

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

Iacoangeli,

Dilliott,

Al Khleifat

et al. 2024

Preprint

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Recently, large-scale case-control analyses have been prioritized in the study of ALS. Yet the same effort has not been put forward to investigate additive moderate phenotypic effects of genetic variants in genes driving ALS risk, despite case-level evidence suggesting a potential oligogenic risk model. Considering its direct clinical and therapeutic implications, a large-scale robust investigation of oligogenicity in ALS is greatly needed. Here, we leveraged the Project MinE ALS Sequencing Consortium genome sequencing datasets of individuals with ALS (n = 6711) and controls (n = 2391) to identify signals of association between oligogenicity in known ALS genes (n=26) and disease risk, as well as clinical outcomes. Applying regression models to a discovery and replication cohort, we observed that the risk imparted from carrying rare variants in multiple known ALS genes was significant and was greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes, such as C9orf72. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, might not follow the same pattern as we did not observe any associations. Our findings represent the first large-scale, case-control assessment of oligogenic associations in ALS to date and confirm that oligogenic events involving known ALS risk genes are indeed relevant for the risk of disease in approximately 6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring the use of comprehensive gene panels even when a potential pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need of a complete genetic profile for the correct choice of therapy in all ALS patients.

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Section: Discussionsupporting

confidence: 91%

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

Iacoangeli,

Dilliott,

Al Khleifat

et al. 2024

Preprint

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“…392 In particular, they observed the propensity of the β4− β6 region to early unfolding and its frequent interactions with the crowders. This could be a crucial factor in comprehending the misfolding and aggregation of SOD1 452,453 in the densely populated cellular environment. The identification of intermediate states during the thermal unfolding, which might be relevant for pathological aggregation, testifies to the most important advantage of computer simulation: the ability to analyze at the atomic level biophysical process.…”

Section: Chemicalmentioning

confidence: 99%

Computational Approaches to Predict Protein–Protein Interactions in Crowded Cellular Environments

Grassmann,

Miotto,

Desantis

et al. 2024

Chem. Rev.

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Investigating protein–protein interactions is crucial for understanding cellular biological processes because proteins often function within molecular complexes rather than in isolation. While experimental and computational methods have provided valuable insights into these interactions, they often overlook a critical factor: the crowded cellular environment. This environment significantly impacts protein behavior, including structural stability, diffusion, and ultimately the nature of binding. In this review, we discuss theoretical and computational approaches that allow the modeling of biological systems to guide and complement experiments and can thus significantly advance the investigation, and possibly the predictions, of protein–protein interactions in the crowded environment of cell cytoplasm. We explore topics such as statistical mechanics for lattice simulations, hydrodynamic interactions, diffusion processes in high-viscosity environments, and several methods based on molecular dynamics simulations. By synergistically leveraging methods from biophysics and computational biology, we review the state of the art of computational methods to study the impact of molecular crowding on protein–protein interactions and discuss its potential revolutionizing effects on the characterization of the human interactome.

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“…7 In the majority of these diseases, the aggregative molecular species can be identified in a small set of proteins whose features are welldefined. This is the case, for instance, of the amyloid β peptide in AD, 8 Superoxide Dismutase 1, TAR DNA-binding protein 43 and RNA-binding protein FUS in ALS [9][10][11] and Transthyretin in ATTR amyloidosis. 12 Interestingly, AL amyloidosis differs from this paradigm because the molecular aggregating species varies in each patient.…”

Section: Introductionmentioning

confidence: 99%

Computational evidences of a misfolding event in an aggregation‐prone light chain preceding the formation of the non‐native pathogenic dimer

Desantis,

Miotto,

Milanetti

et al. 2024

Proteins

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Antibody light chain amyloidosis is a disorder in which protein aggregates, mainly composed of immunoglobulin light chains, deposit in diverse tissues impairing the correct functioning of organs. Interestingly, due to the high susceptibility of antibodies to mutations, AL amyloidosis appears to be strongly patient‐specific. Indeed, every patient will display their own mutations that will make the proteins involved prone to aggregation thus hindering the study of this disease on a wide scale. In this framework, determining the molecular mechanisms that drive the aggregation could pave the way to the development of patient‐specific therapeutics. Here, we focus on a particular patient‐derived light chain, which has been experimentally characterized. We investigated the early phases of the aggregation pathway through extensive full‐atom molecular dynamics simulations, highlighting a structural rearrangement and the exposure of two hydrophobic regions in the aggregation‐prone species. Next, we moved to consider the pathological dimerization process through docking and molecular dynamics simulations, proposing a dimeric structure as a candidate pathological first assembly. Overall, our results shed light on the first phases of the aggregation pathway for a light chain at an atomic level detail, offering new structural insights into the corresponding aggregation process.

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

Cited by 6 publications

References 63 publications

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

Computational Approaches to Predict Protein–Protein Interactions in Crowded Cellular Environments

Computational evidences of a misfolding event in an aggregation‐prone light chain preceding the formation of the non‐native pathogenic dimer

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