Effect of genetic background on onset and disease progression in the SOD1-G93A model of amyotrophic lateral sclerosis

Mancuso, Renzo; Oliván, Sara; Mancera, Pilar; Pastén-Zamorano, Andrea; Manzano, Raquel; Casas, Caty; Osta, Rosario; Navarro, Xavier

doi:10.3109/17482968.2012.662688

Cited by 47 publications

(40 citation statements)

References 39 publications

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“…The double transgenic mice are on a C57BL6 background and this genetic background is associated with longer survival and milder disease phenotype [44][45][46], which is opposite from what we observed in double transgenic mice. Therefore, our results strongly suggest that H63D HFE is a contributing factor in ALS disease pathogenesis.…”

Section: Discussioncontrasting

confidence: 84%

“…Genetic background can influence disease onset, severity, and survival in ALS rodent models independent of transgene copy numbers [44][45][46]. The double transgenic mice are on a C57BL6 background and this genetic background is associated with longer survival and milder disease phenotype [44][45][46], which is opposite from what we observed in double transgenic mice.…”

Section: Discussioncontrasting

confidence: 83%

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H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Keywords:H63D HFE SOD1(G93A) ALS Iron Oxidative stress Gliosis H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90 days (presymptomatic), 110 days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90 days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110 days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.

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Section: Discussioncontrasting

confidence: 84%

Section: Discussioncontrasting

confidence: 83%

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…At 16 weeks of age, there was a 30 % increase in the number of surviving MNs in the spinal cord of both male and female SOD1 animals treated with PRE-084 with respect to untreated animals. We have previously described the progression of spinal MN degeneration of SOD1 G93A mice, showing that the number of surviving MNs per lumbar cord section averaged 37±2 and 33±3 in male and female mice, respectively, at 12 weeks of age, and 16±2 and 20±1 in male and female mice at 16 weeks of age [23,44], respectively. In the present study, we found that PRE-084 treated animals had a mean of 35±1 (males) and 34±2 (females) MNs per section at 16 weeks of age.…”

Section: Discussionmentioning

confidence: 91%

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

et al. 2012

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Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1 G93A mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1 G93A animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca 2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.

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“…Superoxide dismutase 1 (SOD1) is a ubiquitous cytosolic enzyme; mutations in the Cu/Zn Sod1 gene are a common cause of familial cases of this disease [1, 2]. Transgenic mice expressing the mutated human Sod1 gene are used as a classical model of ALS, in terms of both the mechanism and treatment [3, 4]. The mutant gene shows a toxic gain of function phenotype, which leads to paralysis and death from respiratory failure in the animal model [5].…”

Section: Introductionmentioning

confidence: 99%

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis

Deng

Duan

et al. 2018

Cell Physiol Biochem

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Background: Myelination, degeneration and regeneration are implicated in crucial responses to injury in the peripheral nervous system. Considering the progression of amyotrophic lateral sclerosis (ALS), we used the superoxide dismutase 1 (SOD1)-G93A transgenic mouse model of ALS to investigate the effects of mutant SOD1 on the peripheral nerves. Methods: Changes in peripheral nerve morphology were analyzed in SOD1 mutant mice at various stages of the disease by toluidine blue staining and electron microscopy (EM). Schwann cell proliferation and recruitment of inflammatory factors were detected by immunofluorescence staining and quantitative reverse transcription PCR and were compared between SOD1 mutant mice and control mice. Furthermore, western blotting (WB) and TUNEL staining were used to investigate axonal damage and Schwann cell survival in the sciatic nerves of mice in both groups. Results: An analysis of the peripheral nervous system in SOD1-G93A mice revealed the following novel features: (i) Schwann cells and axons in mutant mice underwent changes that were similar to those seen in the control mice during the early development of peripheral nerves. (ii) The peripheral nerves of SOD1-G93A mice developed progressive neuropathy, which presented as defects in axons and myelin, leading to difficulty in walking and reduced locomotor capacity at a late stage of the disease. (iii) Macrophages were recruited and accumulated, and nerve injury and a deficit in the blood-nerve barrier were observed. (iv) Proliferation and the inflammatory micro-environment were inhibited, which impaired the regeneration and remyelination of axons after crush injury in the SOD1-G93A mice. Conclusions: The mutant human SOD1 protein induced axonal and myelin degeneration during the progression of ALS and participated in axon remyelination and regeneration in response to injury.

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Effect of genetic background on onset and disease progression in the SOD1-G93A model of amyotrophic lateral sclerosis

Cited by 47 publications

References 39 publications

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis

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