Is SOD1 loss of function involved in amyotrophic lateral sclerosis?

Abstract

Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a--still unknown--toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1-amyotrophic lateral sclerosis. From analysing published data from patients with SOD1-amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1-amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis.

Keywords: amyotrophic lateral sclerosis; loss of function; motor neuron disease; superoxide dismutase 1.

Figure 1

Diagram of human SOD1 mutations, variants and activity in the current literature. The amino acid sequence of SOD1 is shown, with the location of introns (A). One hundred and fifty-five SOD1 mutations described in patients with ALS are annotated; data are taken from the ALS online database (ALSoD, http://alsod.iop.kcl.ac.uk, January 2013) and additional literature. Note that only variations that are predicted to affect the amino acid sequence of the protein have been included. Pathogenicity has not been shown for all mutations. Mutations listed on ALSoD, InsAexon2 and E133del are the same as mutations V29insA and E133delGAA, respectively, and so have not been annotated separately. Similarly, we believe the mutation D125TT to be L126delTT and mutation E133insTT to be E132inTT. Information about highlighted structural elements was from Wang et al. (2006). Additional references are Pramatarova et al. (1995) and Kobayashi et al. (2012). ^†Locations where two nucleotide changes results in the same amino acid substitution; ^¶Mutations which result in a frameshift and premature stop codon. (B) Diagram of human SOD1 mutations and overall enzyme activity measured in red blood cells, fibroblast and lymphoblast cell lines. Measurements from patients carrying 48 SOD1-familial ALS mutations between 1993 and December 2012; original references are cited in Supplementary Table 1. All measures fall below 100% normal activity. Three mutations found in homozygous individuals are shown on the right hand side of the figure. Red circles show measures of intrinsic activity where these are known. We note that all mutations shown here are familial, not sporadic, and have supporting data indicating they are ALS causative (Supplementary Table 1). Where more than one publication shows overall activity for an individual mutation the value from the report with the highest sample size has been plotted. Refer to supporting references for details. Het = heterozygous; Hom = homozygous.

Figure 2

The cycle of SOD1 loss of function, schematic representation of a potential co-operation between SOD1 loss and gain of function in SOD1–familial ALS pathogenesis. SOD1 loss of function (LOF) increases levels of oxidative stress, which through glutathionylation and oxidation, can facilitate the monomerisation of dimeric SOD1. Once monomerized, SOD1 is more prone to become misfolded, oligomerized and aggregated. The monomerization of previously active dimeric SOD1 and the recruitment of SOD1 into aggregates further enhance the loss of function, feeding back to the beginning of the loop. In this way the gain of function (GOF) effects of misfolded, oligomerized and aggregated SOD1, which are known to cause motor neuron degeneration, are amplified by the loss of function circle. Mutant SOD1 (mutSOD1) has both a direct effect on reduction of SOD1 activity and induces SOD1 misfolding and aggregation. Mislocalisation of both TDP43 and FUS result in misfolding of SOD1. ER = endoplasmic reticulum; MN = motor neuron.