Abstract
BackgroundAn increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.MethodsHere, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology.ResultsWe demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA, and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRβ in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis.ConclusionOur findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.
Highlights
An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS
ALS fibroblasts show aberrant levels of S100A4, mammalian target of rapamycin (mTOR), SQSTM1/p62, and nuclear factor-κB (NF-κB) In a previous study, we demonstrated that S100A4 was increased in fibroblasts from patients with different SOD1 pathogenic variants [59]
To investigate whether an augmented expression of S100A4 is a common trait of fibroblasts derived from patients with ALS, we have analyzed the protein expression in primary fibroblasts from ALS patients without known variants in ALSassociated genes, and from patients carrying pathogenic C9orf72 expansions, the most common cause of familial and sporadic ALS found to date
Summary
An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. Fibroblasts from patients with ALS show numerous abnormalities concerning autophagy, stress response [23, 40, 48, 52], and the stability of RNA transcripts related to oxidative phosphorylation, protein synthesis, and inflammation [65]. These peripheral cells share common pathogenic pathways with different CNS resident cells and represent an accessible model for studying molecular, cellular, and genetic parameters of the pathology [51]
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