A novel p.E121G SOD1 mutation in slowly progressive form of amyotrophic lateral sclerosis induces cytoplasmic aggregates in cultured motor neurons and reduces cell viability

Abstract

Mutations in the SOD1 gene encoding the Cu/Zn superoxide dismutase-1 protein are responsible for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. To date a large number of mutations have been reported in SOD1, but only few of them have been studied and validated by functional studies. We present a novel mutation in SOD1 in a female suffering from slowly progressive ALS. This dominant mutation (c.365A > G) in exon 5 resulted in a substitution of a highly conserved amino acid (p.E121G) of the protein. Functional studies in the motor neuronal cell line NSC34 and in primary culture of mouse motor neurons revealed that this mutation p.E121G induced aggregates positive for SOD1 and ubiquitin, as well as reduced cell viability. These findings identified a novel causal mutation in ALS in close proximity with one of the three histidine residues (H120) of SOD1 interacting with copper.

Key words::

• ALS
• SOD1
• aggregates
• ubiquitin

Acknowledgement

This work was funded by the Association ARSla, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université François Rabelais, Tours and the Région Centre. We thank the technology platform PPF ASB of the Université François Rabelais for technical help.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.