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Molecular dynamics analysis of Superoxide Dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression [preprint]
Authors
Kalia, MunishikhaMiotto, Mattia
Ness, Deborah
Opie-Martin, Sarah
Spargo, Thomas P
Di Rienzo, Lorenzo
Biagini, Tommaso
Petrizzelli, Francesco
Al-Khleifat, Ahmad
Kabiljo, Renata
Topp, Simon
Mayl, Keith
Fogh, Isabella
Mehta, Puja R
Williams, Kelly L
Jockel-Balsarotti, Jennifer
Bali, Taha
Self, Wade
Henden, Lyndal
Nicholson, Garth A
Ticozzi, Nicola
McKenna-Yasek, Diane
Tang, Lu
Shaw, Pamela
Chio, Adriano
Ludolph, Albert
Weishaupt, Jochen H
Landers, John E
Glass, Jonathan D
Mora, Jesus S
Robberecht, Wim
Van Damme, Philip
McLaughlin, Russell
Hardiman, Orla
van den Berg, Leonard H
Veldink, Jan H
Corcia, Phillippe
Stevic, Zorica
Siddique, Nailah
Ratti, Antonia
Silani, Vincenzo
Blair, Ian P
Fan, Dong-sheng
Esselin, Florence
de la Cruz, Elisa
Camu, William
Basak, A Nazli
Siddique, Teepu
Miller, Timothy
Brown, Robert H
Andersen, Peter M
Shaw, Christopher E
Mazza, Tommaso
Ruocco, Giancarlo
Milanetti, Edoardo
Dobson, Richard JB
Al-Chalabi, Ammar
Iacoangeli, Alfredo
UMass Chan Affiliations
NeurologyDocument Type
PreprintPublication Date
2022-12-05
Metadata
Show full item recordAbstract
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. Investigating how different SOD1 variants affect the protein dynamics might help in understanding their pathogenic mechanism and explaining their heterogeneous clinical presentation. 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 are associated with a loss 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, applying graph theory to a network representation of the proteins, we identified differences in the intramolecular contacts of the two classes of variants. Finally, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants from both classes, 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 highlights key differences in the dynamic behaviour of the WTL and MBR SOD1 variants, and wild-type SOD1 at an atomic and molecular level. We identified interesting structural features 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.Source
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, 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, Project MinE ALS Sequencing Consortium, Christopher E Shaw, Tommaso Mazza, Giancarlo Ruocco, Edoardo Milanetti, Richard JB Dobson, Ammar Al-Chalabi, Alfredo Iacoangeli bioRxiv 2022.12.05.519128; doi: https://doi.org/10.1101/2022.12.05.519128DOI
10.1101/2022.12.05.519128Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51566Notes
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Rights
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.; Attribution 4.0 InternationalDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2022.12.05.519128
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Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.