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

Publisher: BioMed Central Country of Publication: England NLM ID: 101222974 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-2094 (Electronic) Linking ISSN: 17422094 NLM ISO Abbreviation: J Neuroinflammation Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2004-

Amyotrophic Lateral Sclerosis/*drug therapy ; Niclosamide/*pharmacology ; Niclosamide/*therapeutic use ; S100 Calcium-Binding Protein A4/*antagonists & inhibitors; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Fibrosis/drug therapy ; Fibrosis/prevention & control ; Humans ; Inflammation/drug therapy ; Inflammation/prevention & control ; Mice ; Mutation ; NF-kappa B/metabolism ; RNA-Binding Protein FUS/genetics ; S100 Calcium-Binding Protein A4/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism

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.

Biol Reprod. 2020 Apr 24;102(5):1011-1019. (PMID: 31950153)
J Cell Physiol. 2018 Mar;233(3):2409-2419. (PMID: 28731277)
Nat Commun. 2019 Aug 28;10(1):3879. (PMID: 31462640)
Cell Death Dis. 2018 Aug 6;9(8):830. (PMID: 30082779)
Nat Rev Neurosci. 2019 Nov;20(11):649-666. (PMID: 31582840)
PLoS One. 2014 Jan 08;9(1):e85887. (PMID: 24416452)
Cancers (Basel). 2018 Jul 23;10(7):. (PMID: 30041429)
Neuron. 2011 Oct 20;72(2):257-68. (PMID: 21944779)
Brain Pathol. 2020 Mar;30(2):272-282. (PMID: 31376190)
FASEB Bioadv. 2020 Jan 03;2(2):77-89. (PMID: 32123858)
Neurobiol Dis. 2020 Feb;134:104674. (PMID: 31731043)
Nat Neurosci. 2021 Feb;24(2):234-244. (PMID: 33526922)
ChemMedChem. 2018 Jun 6;13(11):1088-1091. (PMID: 29603892)
Cell Death Dis. 2018 Feb 15;9(3):277. (PMID: 29449540)
Oxid Med Cell Longev. 2018 May 7;2018:7640272. (PMID: 29854094)
Clin Cancer Res. 2013 Aug 1;19(15):4124-36. (PMID: 23908450)
Physiol Rev. 2019 Apr 1;99(2):1281-1324. (PMID: 30864875)
Oncogene. 2019 Dec;38(50):7473-7490. (PMID: 31444413)
Front Pharmacol. 2017 Mar 10;8:110. (PMID: 28344555)
Ann Neurol. 2020 Mar;87(3):434-441. (PMID: 31916305)
Neurology. 2019 Apr 2;92(14):e1610-e1623. (PMID: 30850440)
Nat Neurosci. 2019 Mar;22(3):421-435. (PMID: 30664769)
Lancet Neurol. 2019 Feb;18(2):211-220. (PMID: 30663610)
N Engl J Med. 2017 Jul 13;377(2):162-172. (PMID: 28700839)
Nat Med. 2018 Mar;24(3):313-325. (PMID: 29400714)
Nat Commun. 2018 Jul 20;9(1):2845. (PMID: 30030424)
Rev Neurosci. 2017 Jul 26;28(5):551-572. (PMID: 28343168)
Neural Regen Res. 2018 Jul;13(7):1185-1186. (PMID: 30028322)
Acta Neuropathol Commun. 2018 Apr 13;6(1):28. (PMID: 29653597)
Nat Cell Biol. 2018 Aug;20(8):917-927. (PMID: 30050118)
Oncotarget. 2016 Jun 7;7(23):34630-42. (PMID: 27127879)
Cell Immunol. 2014 Mar-Apr;288(1-2):15-23. (PMID: 24561310)
J Clin Invest. 2014 Mar;124(3):981-99. (PMID: 24509083)
Neurobiol Dis. 2021 Feb;149:105225. (PMID: 33347974)
Brain Pathol. 2014 Jul;24(4):404-13. (PMID: 24946078)
iScience. 2020 May 22;23(5):101087. (PMID: 32371370)
JCI Insight. 2019 Aug 8;4(15):. (PMID: 31391337)
Neurobiol Dis. 2020 Nov;145:105051. (PMID: 32827688)
Mol Neurodegener. 2017 Oct 24;12(1):76. (PMID: 29065921)
Nat Commun. 2012;3:1197. (PMID: 23149742)
Neurobiol Aging. 2015 May;36(5):2005.e5-2005.e13. (PMID: 25792239)
PLoS One. 2017 May 16;12(5):e0177649. (PMID: 28520806)
Elife. 2019 Feb 12;8:. (PMID: 30747709)
Trends Genet. 2018 Jun;34(6):404-423. (PMID: 29605155)
ACS Med Chem Lett. 2010 Sep 07;1(9):454-9. (PMID: 24900231)
Sci Rep. 2017 May 17;7(1):2033. (PMID: 28515487)
Cells. 2019 Mar 15;8(3):. (PMID: 30875964)
J Cachexia Sarcopenia Muscle. 2019 Aug;10(4):872-893. (PMID: 31020811)
J Immunol. 2017 Mar 1;198(5):1775-1781. (PMID: 28223405)
J Neurol. 2020 May;267(5):1291-1299. (PMID: 31938860)
Nat Commun. 2017 Oct 24;8(1):1130. (PMID: 29066712)
J Cell Mol Med. 2020 Jun;24(11):5973-5983. (PMID: 32307910)
Neural Regen Res. 2020 Nov;15(11):2043-2044. (PMID: 32394958)
PLoS One. 2014 Jun 19;9(6):e100405. (PMID: 24945434)
Life Sci. 2019 Mar 1;220:8-20. (PMID: 30611787)
Rheumatol Int. 2019 Mar;39(3):469-478. (PMID: 30392117)
Acta Neuropathol Commun. 2016 May 05;4(1):47. (PMID: 27151080)
Cell Signal. 2018 Jan;41:89-96. (PMID: 28389414)
Front Immunol. 2020 Aug 14;11:1394. (PMID: 32922384)
Cells. 2019 Oct 16;8(10):. (PMID: 31623154)
Front Neurol. 2017 Dec 15;8:669. (PMID: 29326641)
Dis Model Mech. 2017 Aug 1;10(8):1015-1025. (PMID: 28550101)
Cell Biosci. 2017 Nov 25;7:64. (PMID: 29204268)
Acta Neuropathol Commun. 2019 Jul 5;7(1):107. (PMID: 31277703)
Data Brief. 2021 Feb 11;35:106863. (PMID: 33665258)
Eur J Pharmacol. 2019 Nov 15;863:172673. (PMID: 31542480)
Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):E6993-7002. (PMID: 26621731)
Ann Rheum Dis. 2015 Sep;74(9):1748-55. (PMID: 24709861)
J Natl Cancer Inst. 2011 Jul 6;103(13):1018-36. (PMID: 21685359)
Int J Mol Sci. 2018 Aug 05;19(8):. (PMID: 30081609)
Mol Cancer Res. 2019 Nov;17(11):2184-2195. (PMID: 31427441)
Inflamm Res. 2015 Apr;64(3-4):225-33. (PMID: 25708600)
Genes (Basel). 2020 Sep 24;11(10):. (PMID: 32987860)
Mol Neurodegener. 2020 Aug 15;15(1):45. (PMID: 32799899)

SpliceALS Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica

Keywords: ALS; FUS; Fibroblasts; Inflammation; Neurodegeneration; S100A4; α-SMA

0 (NF-kappa B)
0 (RNA-Binding Protein FUS)
0 (S100 Calcium-Binding Protein A4)
8KK8CQ2K8G (Niclosamide)
EC 2.7.1.1 (MTOR protein, human)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)

Date Created: 20210613 Date Completed: 20220216 Latest Revision: 20220216

20250114

PMC8196441

10.1186/s12974-021-02184-1

34118929