Abstract
Superoxide dismutase 1 (SOD1) is one of the causative genes associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder. SOD1 aggregation contributes to ALS pathogenesis. A fraction of the protein is localized in the nucleus (nSOD1), where it seems to be involved in the regulation of genes participating in the oxidative stress response and DNA repair. Peripheral blood mononuclear cells (PBMCs) were collected from sporadic ALS (sALS) patients (n = 18) and healthy controls (n = 12) to perform RNA-sequencing experiments and differential expression analysis. Patients were stratified into groups with “high” and “low” levels of nSOD1. We obtained different gene expression patterns for high- and low-nSOD1 patients. Differentially expressed genes in high nSOD1 form a cluster similar to controls compared to the low-nSOD1 group. The pathways activated in high-nSOD1 patients are related to the upregulation of HSP70 molecular chaperones. We demonstrated that, in this condition, the DNA damage is reduced, even under oxidative stress conditions. Our findings highlight the importance of the nuclear localization of SOD1 as a protective mechanism in sALS patients.
Highlights
Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the degeneration and loss of cortical, bulbar and spinal motor neurons, culminating in muscle denervation and paralysis
HSF1 becomes trimerized and phosphorylated, and it translocates into the nucleus, where it binds to conserved heat shock-responsive DNA elements (HSEs) to upregulate genes coding for heat shock proteins (HSPs) [28]. The levels of both HSF1 transcript and protein were unaltered (Figure 6G,H), while the phosphorylation of HSF1 protein at S326 was higher in patients with high nSOD1 compared to both low-nSOD1 patients and healthy controls (Figure 6I,J). These results show the greater activation of HSP70 and HSPH1 in Peripheral blood mononuclear cells (PBMCs) of patients with high nSOD1 distribution
Our results clearly indicate that the RNA expression profile of high-nSOD1 patients is more similar to that of healthy controls compared to the low-nSOD1 subgroup
Summary
Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the degeneration and loss of cortical, bulbar and spinal motor neurons, culminating in muscle denervation and paralysis. Cu/Zn superoxide dismutase 1 (SOD1), a homodimeric metalloprotein with antioxidant function, has been identified as one of the pathogenic proteins involved in ALS development. It is mainly distributed in the cytoplasm; it has been found in the nucleus, lysosomes and mitochondria [1]. All protein products of this mutant gene are capable of misfolding and aggregating intracellularly, causing proteotoxic stresses and possibly toxicity. Increased cytoplasmatic aggregation, dimer destabilization and oligomerization are all mechanisms proposed for mutant SOD1 toxicity in ALS, and they might not be mutually exclusive [5,6]
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