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

doi:10.1016/j.csbj.2023.09.016

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 journal › Article › peer-review

3 Citations (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 language	English
Pages (from-to)	5296-5308
Number of pages	13
Journal	Computational and Structural Biotechnology Journal
Volume	21
Early online date	17 Sept 2023
DOIs	https://doi.org/10.1016/j.csbj.2023.09.016
Publication status	Published - 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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Kalia, M., Miotto, M., Ness, D., Opie-Martin, S., Spargo, T. P., Di Rienzo, L., Biagini, T., Petrizzelli, F., Al Khleifat, A., Kabiljo, R., Project MinE ALS Sequencing Consortium, SOD1-ALS clinical and genetic data collection group, Mazza, T., Ruocco, G., Milanetti, E., Dobson, R. JB., Al-Chalabi, A., & Iacoangeli, A. (2023). Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression. Computational and Structural Biotechnology Journal, 21, 5296-5308. https://doi.org/10.1016/j.csbj.2023.09.016

@article{f0c51ed8d3304c31bc5ed899ed6873e2,

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

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, {\textquoteleft}wild-type like{\textquoteright} (WTL) and {\textquoteleft}metal binding region{\textquoteright} (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.",

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

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

note = "Funding Information: We would like to thank Simon Topp, Keith Mayl, Isabella Fogh, Puja R Mehta, Kelly L Williams, Jennifer Jockel-Balsarotti, Taha Bali, Wade Self, Lyndal Henden, Garth A Nicholson, Nicola Ticozzi, Diane McKenna-Yasek, Lu Tang, Pamela Shaw, Adriano Chio, Albert Ludolph, Jochen H Weishaupt, John E Landers, Jonathan D Glass, Jesus S Mora, Wim Robberecht, Philip Van Damme, Russell McLaughlin, Orla Hardiman, Leonard H van den Berg, Jan H Veldink, Phillippe Corcia, Zorica Stevic, Nailah Siddique, Antonia Ratti, Vincenzo Silani, Ian P Blair, Dong-sheng Fan, Florence Esselin, Elisa de la Cruz, William Camu, A Nazli Basak, Teepu Siddique, Timothy Miller, Robert H Brown, Peter M Andersen and Christopher E Shaw for providing and collecting clinical and genetic data of people living with SOD1-ALS. We acknowledge use of the research computing facility at King's College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy's & St. Thomas{\textquoteright} NHS Foundation Trusts and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy's and St Thomas' Charity (TR130505). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King's College London, or the Department of Health and Social Care. We would like to thank people with ALS and their families for their participation in this project. We thank the Project MinE Sequencing Consortium members for their collaboration and support. The authors are supported by South London and Maudsley NHS Foundation Trust; Wellcome Trust ; MND Scotland; Motor Neurone Disease Association; National Institute for Health Research; Darby Rimmer MND Foundation; Spastic Paraplegia Foundation; Rosetrees Trust; Alzheimer{\textquoteright}s Research UK; Italian Ministry of Health and Medical Research Council (MRC). M.M. and G.R. acknowledge support from European Research Council Synergy grant ASTRA (n. 855923 ). G.R acknowledges support from European Innovation Council through its Pathfinder Open Programme, project ivBM-4PAP (grant agreement No 101098989 ). Publisher Copyright: {\textcopyright} 2023",

year = "2023",

doi = "10.1016/j.csbj.2023.09.016",

language = "English",

volume = "21",

pages = "5296--5308",

journal = "Computational and Structural Biotechnology Journal",

publisher = "Research Network of Computational and Structural Biotechnology",

}

Kalia, M, Miotto, M, Ness, D, Opie-Martin, S, Spargo, TP, Di Rienzo, L, Biagini, T, Petrizzelli, F, Al Khleifat, A , Kabiljo, R, Project MinE ALS Sequencing Consortium, SOD1-ALS clinical and genetic data collection group, Mazza, T, Ruocco, G, Milanetti, E, Dobson, RJB , Al-Chalabi, A & Iacoangeli, A 2023, 'Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression', Computational and Structural Biotechnology Journal, vol. 21, pp. 5296-5308. https://doi.org/10.1016/j.csbj.2023.09.016

TY - JOUR

T1 - Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

AU - Kalia, Munishikha

AU - Miotto, Mattia

AU - Ness, Deborah

AU - Opie-Martin, Sarah

AU - Spargo, Thomas P.

AU - Di Rienzo, Lorenzo

AU - Biagini, Tommaso

AU - Petrizzelli, Francesco

AU - Al Khleifat, Ahmad

AU - Kabiljo, Renata

AU - Project MinE ALS Sequencing Consortium

AU - SOD1-ALS clinical and genetic data collection group

AU - Mazza, Tommaso

AU - Ruocco, Giancarlo

AU - Milanetti, Edoardo

AU - Dobson, Richard JB

AU - Al-Chalabi, Ammar

AU - Iacoangeli, Alfredo

N1 - Funding Information: We would like to thank Simon Topp, Keith Mayl, Isabella Fogh, Puja R Mehta, Kelly L Williams, Jennifer Jockel-Balsarotti, Taha Bali, Wade Self, Lyndal Henden, Garth A Nicholson, Nicola Ticozzi, Diane McKenna-Yasek, Lu Tang, Pamela Shaw, Adriano Chio, Albert Ludolph, Jochen H Weishaupt, John E Landers, Jonathan D Glass, Jesus S Mora, Wim Robberecht, Philip Van Damme, Russell McLaughlin, Orla Hardiman, Leonard H van den Berg, Jan H Veldink, Phillippe Corcia, Zorica Stevic, Nailah Siddique, Antonia Ratti, Vincenzo Silani, Ian P Blair, Dong-sheng Fan, Florence Esselin, Elisa de la Cruz, William Camu, A Nazli Basak, Teepu Siddique, Timothy Miller, Robert H Brown, Peter M Andersen and Christopher E Shaw for providing and collecting clinical and genetic data of people living with SOD1-ALS. We acknowledge use of the research computing facility at King's College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy's & St. Thomas’ NHS Foundation Trusts and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy's and St Thomas' Charity (TR130505). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King's College London, or the Department of Health and Social Care. We would like to thank people with ALS and their families for their participation in this project. We thank the Project MinE Sequencing Consortium members for their collaboration and support. The authors are supported by South London and Maudsley NHS Foundation Trust; Wellcome Trust ; MND Scotland; Motor Neurone Disease Association; National Institute for Health Research; Darby Rimmer MND Foundation; Spastic Paraplegia Foundation; Rosetrees Trust; Alzheimer’s Research UK; Italian Ministry of Health and Medical Research Council (MRC). M.M. and G.R. acknowledge support from European Research Council Synergy grant ASTRA (n. 855923 ). G.R acknowledges support from European Innovation Council through its Pathfinder Open Programme, project ivBM-4PAP (grant agreement No 101098989 ). Publisher Copyright: © 2023

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - Diseaseassociated SOD1 mutations

KW - Molecular dynamics (MD) simulations

KW - Performed principal component analysis

KW - Superoxide Dismutase type 1 (SOD1)

KW - Survival analysis

UR - http://www.scopus.com/inward/record.url?scp=85175446336&partnerID=8YFLogxK

U2 - 10.1016/j.csbj.2023.09.016

DO - 10.1016/j.csbj.2023.09.016

M3 - Article

AN - SCOPUS:85175446336

VL - 21

SP - 5296

EP - 5308

JO - Computational and Structural Biotechnology Journal

JF - Computational and Structural Biotechnology Journal

ER -

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

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