Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis

Journal of Neuroinflammation, 2021 · DOI: https://doi.org/10.1186/s12974-021-02184-1 · Published: June 9, 2021

Immunology Neurology Research Methodology & Design

Simple Explanation

This study investigates the role of S100A4, a pro-inflammatory and profibrotic factor, in amyotrophic lateral sclerosis (ALS). It demonstrates that S100A4 underlies impaired autophagy and a profibrotic phenotype in ALS fibroblasts. The research also explores the potential of niclosamide, an FDA-approved drug, to target S100A4 and alleviate ALS-related mechanisms. Niclosamide treatment reduces the expression of S100A4, α-SMA, and PDGFRβ in the spinal cord of ALS-FUS mice. The study concludes that S100A4 plays a significant role in ALS pathology and that drugs like niclosamide, which can target inflammatory and fibrotic pathways, could be promising therapeutic tools for ALS.

Study Duration

Not specified

Participants

ALS patients fibroblasts, healthy controls, hFUS mice

Evidence Level

Not specified

Key Findings

1
S100A4 is upregulated in fibroblasts from ALS patients, regardless of the specific gene mutation, suggesting it is a common pathological trait.
2
Silencing S100A4 in ALS fibroblasts leads to decreased expression of key markers associated with autophagy impairment, inflammation, and fibrosis, such as mTOR, SQSTM1/p62, STAT3, N-cadherin and α-SMA.
3
In vivo treatment with niclosamide in ALS-FUS mice reduces the expression of S100A4, α-SMA and PDGFRβ in the spinal cord, reduces gliosis and axonal impairment, and promotes muscle regeneration and reduces fibrosis.

Research Summary

The study demonstrates that S100A4 is upregulated in fibroblasts from ALS patients and in the spinal cord of hFUS mice, suggesting it is a common pathological trait of ALS. Silencing S100A4 in ALS fibroblasts reduces inflammatory, autophagic, and profibrotic pathways and interferes with pathogenic markers such as mTOR, SQSTM1/p62, STAT3, α-SMA and NF-κB. Niclosamide treatment in ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRβ in the spinal cord, reduces gliosis and axonal impairment, and promotes muscle regeneration and reduces fibrosis, showing beneficial effects on muscle atrophy.

Practical Implications

Therapeutic Target

S100A4 is identified as a potential therapeutic target for ALS, given its role in inflammation and fibrosis.

Drug Repurposing

Niclosamide, an FDA-approved drug, shows promise as a potential treatment for ALS due to its ability to target S100A4 and mitigate ALS-related pathologies.

Multifaceted Treatment

The study suggests that an effective ALS treatment may need to be multifunctional and multitargeted, addressing inflammatory, autophagic, and profibrotic mechanisms.

Study Limitations

1
The analysis is based on a small number of patients for each ALS subgroup.
2
The study relies on fibroblast models, which have limitations in fully representing the complexity of ALS.
3
Further research is needed to validate these findings in additional ALS models and with dose-response treatments.

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