Abstract
In 1993, Rosen and collaborators discovered that the gene encoding SOD1 has mutations in amyotrophic lateral sclerosis (ALS) patients; moreover, these mutations are found in the exon regions, suggesting that their toxic effects are the consequence of protein dysfunction with an increase of oxidative stress. While a clear genetic picture has been delineated, a more complex scenario has been ascribed to the SOD1 protein. On the one hand, some evidence sustains the hypothesis of an additionally toxic role for wild-type SOD1 (WT-SOD1) in the pathogenesis of sporadic ALS. On the other hand, our group identified a discrepancy among WT-SOD1 protein expression levels and mRNA in ALS sporadic patients, thus providing the hypothesis of a re-localization of the “missing” SOD1 in a different sub-cellular compartment, i.e., nucleus, or an aggregation/precipitation in the insoluble fraction. Moreover, our data also indicate an association between longer disease duration and higher amounts of soluble SOD1 within the nucleus, suggesting a possible defensive role of the protein in this compartment. Starting from this evidence, in this review we will attempt to resolve the “ambivalent” behavior of SOD1 in ALS disease and we will try to classify sporadic ALS patients according to a novel biological signature, i.e., SOD localization.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder characterized by the progressive loss of motor neurons in the brain, brainstem, and spinal cord, which culminates in paralysis and death within a few years of diagnosis
Similar to Tsang and colleagues (2014) [57], who suggested that Superoxide Dismutase 1 (SOD1) acts as a nuclear transcription factor to regulate oxidative stress resistance, we proposed a possible mechanism of action of SOD1
SOD1 has been broadly studied in different models since the discovery of its involvement in ALS disease
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder characterized by the progressive loss of motor neurons in the brain, brainstem, and spinal cord, which culminates in paralysis and death within a few years of diagnosis. Death occurs within 3–5 years from disease onset mainly caused by respiratory paralysis, but extreme cases with patients’ survival >40 years have recently been reported [1]. Starting from SOD1, whose discovery in 1993 made it the first ALS gene to be identified [3], at least 25 genes have been implicated in familial ALS (fALS), sporadic ALS (sALS), or both. The human SOD1 gene (Entrez Gene ID 6647) is located on chromosome 21q22.11, and it codes for the monomeric SOD1 protein (153 aamino aacciids, mmolecular weight 16 kkDDa). Ons of the SOD1 gene, pointing out that STOhDe m1 toosxticcoemffemcotsnamreutthaetiroenssuflotsuonfdpirnottheienS’sOfDai1lugreens e[1a6r]e.
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