Molecular dynamics analysis of Superoxide Dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression
Authors: Kalia Munishikha , Miotto 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 ,   Project MinE ALS Sequencing Consortium, Shaw Christopher E , Mazza Tommaso , Ruocco Giancarlo , Milanetti Edoardo , Dobson Richard JB , Al-Chalabi Ammar , Iacoangeli Alfredo 
Published: December 2022

ABSTRACTMutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS.SOD1variants express high phenotypic variability and over 200 have been reported in people with ALS. Investigating how differentSOD1variants 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 500SOD1ALS 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 ofSOD1ALS, and an involvement of loss-of-function of SOD1 with the disease progression.