Mutant Cu/Zn Superoxide Dismutase (A4V) Turnover Is Altered in Cells Containing Inclusions

Natalie E Farrawell; Justin J Yerbury

doi:10.3389/fnmol.2021.771911

Mutant Cu/Zn Superoxide Dismutase (A4V) Turnover Is Altered in Cells Containing Inclusions

Front Mol Neurosci. 2021 Nov 3:14:771911. doi: 10.3389/fnmol.2021.771911. eCollection 2021.

Authors

Natalie E Farrawell^{1

2}, Justin J Yerbury^{1

2}

Affiliations

¹ Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
² School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia.

Abstract

SOD1 mutations account for ∼20% of familial amyotrophic lateral sclerosis (ALS) cases in which the hallmark pathological feature is insoluble SOD1 aggregates within motor neurons. Here, we investigated the degradation and synthesis of mutant SOD1 to determine whether the aggregation of mutant SOD1^A4V affects these processes. We confirm that, in general, the degradation of mutant SOD1^A4V occurs at a significantly faster rate than wild-type SOD1. We also report that the turnover and synthesis of mutant SOD1^A4V is impaired in the presence of insoluble SOD1^A4V aggregates. However, the timing of aggregation of SOD1^A4V did not coincide with UPS dysfunction. Together, these results reveal the impact of SOD1 aggregation on protein degradation pathways, highlighting the importance of the UPS in preventing neurodegenerative disorders such as ALS.

Keywords: ALS; SOD1; UPR – unfolded protein response; UPS – ubiquitin proteasome system; proteome homeostasis.