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Implications of fALS Mutations on Sod1 Function and Oligomerization in Cell Models

Lookup NU author(s): Professor Tiago OuteiroORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 The Author(s) Among the familial forms of amyotrophic lateral sclerosis (fALS), 20% are associated with the Cu,Zn-superoxide dismutase (Sod1). fALS is characterized by the accumulation of aggregated proteins and the increase in oxidative stress markers. Here, we used the non-invasive bimolecular fluorescence complementation (BiFC) assay in human H4 cells to investigate the kinetics of aggregation and subcellular localization of Sod1 mutants. We also studied the effect of the different Sod1 mutants to respond against oxidative stress by following the levels of reactive oxygen species (ROS) after treatment with hydrogen peroxide. Our results showed that only 30% of cells transfected with A4VSod1 showed no inclusions while for the other Sod1 mutants tested (L38V, G93A and G93C), this percentage was at least 70%. In addition, we found that 10% of cells transfected with A4VSod1 displayed more than five inclusions per cell and that A4V and G93A Sod1 formed inclusions more rapidly than L38V and G93C Sod1. Expression of WTSod1 significantly decreased the intracellular oxidation levels in comparison with expression of fALS Sod1 mutants, suggesting the mutations induce a functional impairment. All fALS mutations impaired nuclear localization of Sod1, which is important for maintaining genomic stability. Consistently, expression of WTSod1, but not of fALS Sod1 mutants, reduced DNA damage, as measured by the comet assay. Altogether, our study sheds light into the effects of fALS Sod1 mutations on inclusion formation, dynamics, and localization as well as on antioxidant response, opening novel avenues for investigating the role of fALS Sod1 mutations in pathogenesis.

Publication metadata

Author(s): Brasil AA, Magalhães RSS, de Carvalho MDC, Paiva I, Gerhardt E, Pereira MD, Outeiro TF, Eleutherio ECA

Publication type: Article

Publication status: Published

Journal: Molecular Neurobiology

Year: 2018

Volume: 55

Issue: 6

Pages: 5269-5281

Print publication date: 01/06/2018

Online publication date: 07/09/2017

Acceptance date: 23/08/2017

Date deposited: 20/12/2017

ISSN (print): 0893-7648

ISSN (electronic): 1559-1182

Publisher: Humana Press Inc.


DOI: 10.1007/s12035-017-0755-4


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