Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that causes motor neuron (MN) loss and skeletal muscle paralysis. It is uncertain whether this degeneration of MNs is triggered intrinsically and is autonomous, or if the disease initiating mechanisms are extrinsic to MNs. We hypothesized that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. Some inherited forms of ALS are caused by mutations in the superoxide dismutase-1 (SOD1) gene, that encodes an antioxidant protein, so we created transgenic (tg) mice expressing wild-type-, G37R-, and G93A-human SOD1 gene variants only in skeletal muscle. Presence of human SOD1 (hSOD1) protein in skeletal muscle was verified by western blotting, enzyme activity gels, and immunofluorescence in myofibers and satellite cells. These tg mice developed limb weakness and paresis with motor deficits, limb and chest muscle wasting, diaphragm atrophy, and age-related fatal disease with a lifespan shortening of 10–16%. Brown and white adipose tissue also became wasted. Myofibers of tg mice developed crystalline-like inclusions, individualized sarcomere destruction, mitochondriopathy with vesiculation, DNA damage, and activated p53. Satellite cells became apoptotic. The diaphragm developed severe loss of neuromuscular junction presynaptic and postsynaptic integrity, including decreased innervation, loss of synaptophysin, nitration of synaptophysin, and loss of nicotinic acetylcholine receptor and scaffold protein rapsyn. Co-immunoprecipitation identified hSOD1 interaction with rapsyn. Spinal cords of tg mice developed gross atrophy. Spinal MNs formed cytoplasmic and nuclear inclusions, axonopathy, mitochondriopathy, accumulated DNA damage, activated p53 and cleaved caspase-3, and died. Tg mice had a 40–50% loss of MNs. This work shows that hSOD1 in skeletal muscle is a driver of pathogenesis in ALS, that involves myofiber and satellite cell toxicity, and apparent muscle-adipose tissue disease relationships. It also identifies a non-autonomous mechanism for MN degeneration explaining their selective vulnerability as likely a form of target-deprivation retrograde neurodegeneration.

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“…There is growing evidence that WT SOD1 can be pathogenic in ALS (7,12,13,(87)(88)(89). Interestingly, our WT hSOD1 mus tg mice developed disease.…”

Section: Discussionmentioning

confidence: 66%

Skeletal Muscle-Restricted Expression of Human SOD1 in Transgenic Mice Causes a Fatal ALS-Like Syndrome

Martin

Wong

2020

Front. Neurol.

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“…However, any genetic risk factors or family history in sALS has not been suggested clearly until now, although ALS-related genes (TAR DNA binding protein; TDP-43, Fused in Sarcoma; FUS and Chromosome 9 open reading frame 72; C9orf72) have been linked to sALS 12 – 16 . Interestingly, inclusion of wild-type (WT)-SOD1 are detected in sALS patients and mouse models with WT-SOD1 overexpression 17 – 22 . The pathological modification of WT-SOD1 by mutant SOD1 or sALS-related proteins like TDP43 and FUS has been reported 11 , 14 , 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

Novel chemical inhibitor against SOD1 misfolding and aggregation protects neuron-loss and ameliorates disease symptoms in ALS mouse model

et al. 2021

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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu, Zn-superoxide dismutase (SOD1) causing the gain of its toxic property are the major culprit of familial ALS (fALS). The abnormal SOD1 aggregation in the motor neurons has been suggested as the major pathological hallmark of ALS patients. However, the development of pharmacological interventions against SOD1 still needs further investigation. In this study, using ELISA-based chemical screening with wild and mutant SOD1 proteins, we screened a new small molecule, PRG-A01, which could block the misfolding/aggregation of SOD1 or TDP-43. The drug rescued the cell death induced by mutant SOD1 in human neuroblastoma cell line. Administration of PRG-A01 into the ALS model mouse resulted in significant improvement of muscle strength, motor neuron viability and mobility with extended lifespan. These results suggest that SOD1 misfolding/aggregation is a potent therapeutic target for SOD1 related ALS.

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“…SOD1 itself is an enzyme whose canonical role is the protective neutralization of reactive oxygen species within cells. While the preponderance of evidence suggests that abnormal, cytotoxic protein aggregation and mitochondrial dysfunction stemming from SOD1 mutations drives pathology in these cases ( Furukawa and Tokuda, 2020 ; Tak et al, 2020 ), it is important to note from a clinical standpoint that KO animal studies have shown SOD1 not to be dispensable ( Sakellariou et al, 2018 ). In fact, loss-of-function mechanisms may play as serious a role as any other factor contributing to ALS pathology, so it is therefore unrealistic to expect that simply eliminating mutant SOD1 will be adequate in human gene therapy for ALS [comprehensively reviewed by Kim et al (2020) ].…”

Section: Introductionmentioning

confidence: 99%

A Single Transcript Knockdown-Replacement Strategy Employing 5’ UTR Secondary Structures to Precisely Titrate Rescue Protein Translation

et al. 2022

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One overarching goal of gene therapy is the replacement of faulty genes with functional ones. A significant hurdle is presented by the fact that under- or over-expression of a protein may cause disease as readily as coding mutations. There is a clear and present need for pipelines to translate experimentally validated gene therapy strategies to clinical application. To address this we developed a modular, single-transgene expression system for replacing target genes with physiologically expressed variants. In order to accomplish this, we first designed a range of 5’ UTR “attenuator” sequences which predictably diminish translation of the paired gene. These sequences provide wide general utility by allowing control over translation from high expression, ubiquitous promoters. Importantly, we demonstrate that this permits an entirely novel knockdown and rescue application by pairing microRNA-adapted shRNAs alongside their respective replacement gene on a single transcript. A noteworthy candidate for this corrective approach is the degenerative and uniformly fatal motor neuron disease ALS. A strong proportion of non-idiopathic ALS cases are caused by varied mutations to the SOD1 gene, and as clinical trials to treat ALS are being initiated, it is important to consider that loss-of-function mechanisms contribute to its pathology as strongly as any other factor. As a generalized approach to treat monogenic diseases caused by heterogeneous mutations, we demonstrate complete and predictable control over replacement of SOD1 in stable cell lines by varying the strength of attenuators.

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Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Cited by 27 publications

References 120 publications

Skeletal Muscle-Restricted Expression of Human SOD1 in Transgenic Mice Causes a Fatal ALS-Like Syndrome

Skeletal Muscle-Restricted Expression of Human SOD1 in Transgenic Mice Causes a Fatal ALS-Like Syndrome

Novel chemical inhibitor against SOD1 misfolding and aggregation protects neuron-loss and ameliorates disease symptoms in ALS mouse model

A Single Transcript Knockdown-Replacement Strategy Employing 5’ UTR Secondary Structures to Precisely Titrate Rescue Protein Translation

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