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

Abstract

Background 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. 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. Methods Here, 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. Results We 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. Conclusion Our 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.

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

“…WNT1 [182], NRGN (neurogranin) [183], CCK (cholecystokinin) [184], RGS4 [185], PLK2 [186], LINGO1 [187], UNC5D [188], MEF2D [189], CX3CL1 [190], PIN1 [191], RET (ret proto-oncogene) [192], NME1 [193], STX1B [194], CDK5 [195], NPTX2 [196], VAMP2 [197], PRKAR1B [198], CAP2 [150], SNCB (synuclein beta) [199], AP2M1 [200], S100A9 [201], TLR8 [202], SERPINA1 [203], CCR5 [204], NOD2 [205], TLR7 [202], HGF (hepatocyte growth factor) [206], TLR2 [207], PTPRC (protein tyrosine phosphatase receptor type C) [208], C3 [209], LAMP3 [210], GLI1 [211], GPR4 [212], TLR1 [213], OSMR (oncostatin M receptor) [214], NFATC2 [215], GPNMB (glycoprotein nmb) [216], NQO1 [217], B2M [218], TRDN (triadin) [219], HK2 [220], NEDD4 [221], ATP6 [222], COX2 [223], CASP6 [224], MYD88 [225], NFKBIA (NFKB inhibitor alpha) [226], IL13RA1 [227], ND1 [228], TP53INP1 [229], CSF1 [230], ITPKB (inositol-trisphosphate 3-kinase B) [231], ANXA1 [232], SUMO4 [233], ITGA8 [234] and REST (RE1 silencing transcription factor) [235] have been shown to be activated in PD . WNT1 [236], RTN4R [237], MEF2D [238], CX3CL1 [239], PIN1 [240], UNC13A [241], CDK5 [242], SLC30A3 [243], TUBA4A [244], BCL2A1 [245], CHI3L1 [246], SERPINA1 [247], CCR5 [248], C7 [249], S100A4 [250], C1QB [251], SPP1 [252], TLR7 [253], TLR2 [...…”

Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle

“…This drug interferes with different markers of the disease, such as mTOR, STAT3, and NF-κB. Thus, it reduces inflammation and aggregates formation in skeletal muscle, and displays beneficial effects also on muscle atrophy, by promoting regeneration [99]. It has been found that mutations of SOD1 induce upregulation of c-Abl, an apoptosis-related gene, and a decrease of cell viability.…”

Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models

“…We previously demonstrated that niclosamide inhibits microglia reactivity and migration; it reduces inflammation and fibrosis and promotes autophagy in familial and sporadic ALS fibroblasts [ 19 ]. Moreover, in a proof-of-concept experiment, niclosamide inhibited gliosis and fibrosis in the spinal cord and in the sciatic nerve, promoted regeneration, and reduced fibrosis and inflammation in the skeletal muscles of a small cohort of ALS mice [ 19 ].…”