Mutations were identified in the Cu/Zn superoxide dismutase gene (SOD1) in approximately 15% of patients with familial amyotrophic lateral sclerosis. Transgenic animals expressing mutant SOD1 in all tissues develop an ALS-like phenotype. To determine whether neuron-specific expression of mutant SOD1 is sufficient to produce such a phenotype, we generated transgenic animals carrying the G37R mutation that is associated with the familial form of ALS (FALS), which is driven by the neurofilament light chain promoter. The transgenic animals express high levels of the human SOD1 protein in neuronal tissues, especially in the large motor neurons of the spinal cord, but they show no apparent motor deficit at up to 1.5 years of age. Our animal model suggests that neuron-specific expression of ALS-associated mutant human SOD1 may not be sufficient for the development of the disease in mice.

https://www.jneurosci.org/content/jneuro/21/10/3369.full.pdf

Neuron-Specific Expression of Mutant Superoxide Dismutase 1 in Transgenic Mice Does Not Lead to Motor Impairment

Four-hundred and fifty-one blood samples from Scandinavian patients with motor neuron disease were analysed for mutations in the CuZn-superoxide dismutase gene. Forty-one (9.6%) of the 427 patients with the amyotrophic lateral sclerosis (ALS) form of the disease were found to have a disease-associated mutation, and 14 of these patients were apparently sporadic cases. A mutation was found in 12 of the 51 families with recognized familial ALS. The five different mutations found (Ala4Val, Val14Gly, Asp76Tyr, Asp90Ala, Gly127insTGGG) have different genetic characteristics and are associated with very variable phenotypes spanning from rapidly progressing disease with only lower motor neuron signs to very slowly progressing disease with both the upper and lower motor neuron systems affected. The patients showed different sites of onset, though the progressive bulbar palsy form of the disease appears to be rare among patients with a CuZn-superoxide dismutase mutation. The progression of motor signs and symptoms followed the same basic pattern in patients with different mutations. Extra-motor system symptoms were frequent among patients with a CuZn-superoxide dismutase mutation. The results suggest that patients with mutations in the CuZn-superoxide dismutase gene constitute one disease entity. The Val14Gly and Asp76Tyr mutations have not been reported before, and the latter is the first mutation to be found in exon 3 of the CuZn-superoxide dismutase gene.

Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia.

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.

Is SOD1 loss of function involved in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by degeneration of motor neurons in the brain and spinal cord. Identification of mutations in the gene for Cu,Zn superoxide dismutase (SOD1) in a subset of ALS families made it possible to develop a transgenic mouse model of ALS and to investigate its pathogenesis. These investigations suggest that mutant SOD1 acts through a toxic gain of function which may involve generation of free radicals. Conformational change in the mutant SOD1 protein, especially the distortion of the 'rim' of the electrostatic guidance channel may be central to this toxic gain of function and to the pathogenesis of ALS.

/pdf/genetics-of-amyotrophic-lateral-sclerosis-4xpnuylchi.pdf

Genetics of amyotrophic lateral sclerosis.

J. Neurochem. (2010) 113, 1188–1199.



Abstract

The finding of a secretion pathway and toxicity for mutant superoxide dismutase 1 (SOD1) raised up the possibility of using immunization approaches to reduce or neutralize the burden of toxic SOD1 species in the nervous system. Here we tested a passive immunization approach based on intracerebroventricular infusion in G93A-SOD1 mice of monoclonal antibodies specific to misfolded forms of SOD1 (mSOD1). We tested two monoclonal antibodies that bind distinct epitopes in mSOD1 and that do not bind to intact wild-type (WT) SOD1. One antibody succeeded in reducing the level of mSOD1 by 23% in the spinal cord and in prolonging the lifespan of G93A-SOD1 mice in proportion to the duration of treatment. However, another monoclonal antibody binding to a different SOD1 epitope failed to confer protection indicating that not all anti-SOD1 antibodies might be suitable for immunotherapy. Interestingly, the variable Fab fragment of an anti-SOD1 antibody was sufficient to confer some protection in G93A-SOD1 mice. The partial dispensability of Fc region should offer some advantages for development of immunotherapy with antibodies of smaller molecular size and low immunogenicity. From these results, we propose that passive immunization strategies should be considered as potential avenues for treatment of familial amyotrophic lateral sclerosis caused by SOD1 mutations.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2010.06683.x

Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS

Androgen receptor gene polymorphisms in amyotrophic lateral sclerosis

Summary Amyotrophic lateral sclerosis (ALS) isafatal neurodegenerative disorder affecting motor neurons. Although most cases ofALSaresporadic, -10%areinherited asanautosomal dominant trait. Mutations intheCu/Znsuperoxidedismutase gene (SOD1)areresponsible forafraction offamilial ALS(FALS). Screening ourFALSkindreds by SSCP, wehave identified mutations in15families, ofwhich 9havenotbeenpreviously reported. Twoofthenew mutations alter aminoacids that havenever beenimplicated inFALS.Oneofthemaffects ahighly conserved amino acid involved indimer contact, andtheother one affects theactive-site loop oftheenzyme. These twomutations reduce significantly SOD 1 enzyme activity in lymphoblasts. Ourresults suggest that SOD1mutations areresponsible for > 13%ofFALScases.

Identification ofNew Mutations intheCu/ZnSuperoxide Dismutase GeneofPatients withFamilial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons Although most cases of ALS are sporadic, approximately 10% are inherited as an autosomal dominant trait Mutations in the Cu/Zn superoxide dismutase gene (SOD 1) are responsible for a fraction of familial ALS (FALS) Screening our FALS kindreds by SSCP, we have identified mutations in 15 families, of which 9 have not been previously reported Two of the new mutations alter amino acids that have never been implicated in FALS One of them affects a highly conserved amino acid involved in dimer contact, and the other one affects the active-site loop of the enzyme These two mutations reduce significantly SOD 1 enzyme activity in lymphoblasts Our results suggest that SOD 1 mutations are responsible for > or = 13% of FALS cases

Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis.

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Androgen receptor gene polymorphisms in amyotrophic lateral sclerosis

Identification ofNew Mutations intheCu/ZnSuperoxide Dismutase GeneofPatients withFamilial Amyotrophic Lateral Sclerosis

Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis.