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

Abstract

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.

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

“…SCs in ALS expressed significant levels of CSF1, IL‐34, and SCF and spatially interacted with immune effector cells bearing CSF‐1R and c‐Kit, suggesting a complex cellular interplay leading to local inflammation. Previous studies have shown infiltrating macrophages, mast cells and neutrophils (Chiu et al, ; Nardo et al, ; Trias et al, ) as well as SC proliferation (Deng et al, ) in the sciatic nerve of rodent ALS models. Here, we identified that these immune effectors express CSF‐1R and c‐Kit in human ALS nerves.…”

FGF9 modulates Schwann cell myelination in developing nerves and induces a pro‐inflammatory environment during injury

“…On the second day, the sections were incubated with the secondary antibody and the third antibody, then incubated for 2 minutes with diaminobenzidine solution and observed under a microscope. In addition, the gastrocnemius muscle and tibialis anterior muscle were cut into 10 μm sections and stained with hematoxylin and eosin, as previously described …”

“…In addition, the gastrocnemius muscle and tibialis anterior muscle were cut into 10 μm sections and stained with hematoxylin and eosin, as previously described. 17…”

Endogenus Toxicology: Modern Physio- Pathological Aspects and Relationship with New Therapeutic Strategies. An Integrative Discipline Incorporating Concepts from Different Research Discipline Like Biochemistry, Pharmacology and Toxicology

“…Proliferation and the inflammatory micro-environment were inhibited, which impaired the regeneration and remyelination of axons after crush injury in the SOD1-G93A mice. The mutant human SOD1 protein induced axonal and myelin degeneration during the progression of ALS and participated in axon remyelination -regeneration in response to injury [32].…”