{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T19:38:37Z","timestamp":1781897917614,"version":"3.54.5"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no modifying treatments available. The molecular mechanisms underpinning disease pathogenesis are not fully understood. Recent studies have employed co-expression networks to identify key genes, known as \u201cswitch genes\u201d, responsible for dramatic transcriptional changes in the blood of ALS patients. In this study, we directly investigate the root cause of ALS by examining the changes in gene expression in motor neurons that degenerate in patients. Co-expression networks identified in ALS patients\u2019 spinal cord motor neurons revealed 610 switch genes in seven independent microarrays. Switch genes were enriched in several pathways, including viral carcinogenesis, PI3K-Akt, focal adhesion, proteoglycans in cancer, colorectal cancer, and thyroid hormone signaling. Transcription factors ELK1 and GATA2 were identified as key master regulators of the switch genes. Protein-chemical network analysis identified valproic acid, cyclosporine, estradiol, acetaminophen, quercetin, and carbamazepine as potential therapeutics for ALS. Furthermore, the chemical analysis identified metals and organic compounds including, arsenic, copper, nickel, and benzo(a)pyrene as possible mediators of neurodegeneration. The identification of switch genes provides insights into previously unknown biological pathways associated with ALS.<\/jats:p>","DOI":"10.3389\/fnmol.2022.825031","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T09:33:40Z","timestamp":1647336820000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons"],"prefix":"10.3389","volume":"15","author":[{"given":"Virginie","family":"Bottero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Santiago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith A.","family":"Potashkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1111\/j.1471-4159.2012.07711.x","article-title":"Activation of Elk-1 participates as a neuroprotective compensatory mechanism in models of Huntington\u2019s disease","volume":"121","author":"Anglada-Huguet","year":"2012","journal-title":"J. Neurochem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1677\/JME-10-0122","article-title":"Selective estrogen receptor modulators as brain therapeutic agents","volume":"46","author":"Arevalo","year":"2011","journal-title":"J. Mol. Endocrinol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1002\/0470870818.ch16","article-title":"The female sex hormone oestrogen as neuroprotectant: activities at various levels","volume":"230","author":"Behl","year":"2000","journal-title":"Novartis Found. Symp."},{"key":"B4","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1002\/ana.25276","article-title":"Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion","volume":"84","author":"Benatar","year":"2018","journal-title":"Ann. Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"35899","DOI":"10.1074\/jbc.M112.366419","article-title":"The peroxisome proliferator-activated receptor gamma (PPARgamma) controls natural protective mechanisms against lipid peroxidation in amyotrophic lateral sclerosis","volume":"287","author":"Benedusi","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1021\/acschemneuro.9b00677","article-title":"Quercetin and baicalein act as potent antiamyloidogenic and fibril destabilizing agents for SOD1 fibrils","volume":"11","author":"Bhatia","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.jns.2014.03.005","article-title":"Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis","volume":"340","author":"Boll","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1136\/jnnp-2012-303768","article-title":"Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis","volume":"84","author":"Boylan","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/ana.24304","article-title":"Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice","volume":"77","author":"Butovsky","year":"2015","journal-title":"Ann. Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000315405","article-title":"The association of exposure to lead, mercury and selenium and the development of amyotrophic lateral sclerosis and the epigenetic implications","volume":"8","author":"Callaghan","year":"2011","journal-title":"Neurodegener. Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/s10571-013-9908-9","article-title":"Neuroprotective effects of estradiol on motoneurons in a model of rat spinal cord embryonic explants","volume":"33","author":"Cardona-Rossinyol","year":"2013","journal-title":"Cell Mol. Neurobiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"14759","DOI":"10.1038\/s41598-020-71813-1","article-title":"The effectiveness of nonsteroidal anti-inflammatory drugs and acetaminophen in reduce the risk of amyotrophic lateral sclerosis? A meta-analysis","volume":"10","author":"Chang","year":"2020","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.jns.2007.10.024","article-title":"Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice","volume":"268","author":"Choi","year":"2008","journal-title":"J. Neurol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"D239","DOI":"10.1093\/nar\/gkv1258","article-title":"miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database","volume":"44","author":"Chou","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"D296","DOI":"10.1093\/nar\/gkx1067","article-title":"miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions","volume":"46","author":"Chou","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e0127376","DOI":"10.1371\/journal.pone.0127376","article-title":"C9ORF72 GGGGCC expanded repeats produce splicing dysregulation which correlates with disease severity in amyotrophic lateral sclerosis","volume":"10","author":"Cooper-Knock","year":"2015","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.neurol.2015.11.002","article-title":"Epidemiology of amyotrophic lateral sclerosis: a review of literature","volume":"172","author":"Couratier","year":"2016","journal-title":"Rev. Neurol. (Paris)"},{"key":"B18","first-page":"e9872","article-title":"Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS)","volume-title":"PLoS One","author":"Cox","year":"2010"},{"key":"B19","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1002\/mus.21260","article-title":"Long-term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis","volume":"39","author":"Crochemore","year":"2009","journal-title":"Muscle Nerve"},{"key":"B20","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1152\/physiolgenomics.00087.2001","article-title":"Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter","volume":"16","author":"Dangond","year":"2004","journal-title":"Physiol. Genomics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"6938","DOI":"10.3390\/ijms21186938","article-title":"Genome wide analysis points towards subtype-specific diseases in different genetic forms of amyotrophic lateral sclerosis","volume":"21","author":"Dash","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1111\/ene.13465","article-title":"The role of pre-morbid diabetes on developing amyotrophic lateral sclerosis","volume":"25","author":"D\u2019Ovidio","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e37885","DOI":"10.1371\/journal.pone.0037885","article-title":"A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis","volume":"7","author":"Dupuis","year":"2012","journal-title":"PLoS One"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1007\/s00702-014-1293-0","article-title":"Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study","volume":"122","author":"Durrenberger","year":"2015","journal-title":"J. Neural Transm. (Vienna)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1007\/s00401-012-1027-z","article-title":"Selection of novel reference genes for use in the human central nervous system: a BrainNet Europe study","volume":"124","author":"Durrenberger","year":"2012","journal-title":"Acta Neuropathol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1196\/annals.1347.008","article-title":"Development of 17\u03b1-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study","volume":"1052","author":"Dykens","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.neuroscience.2008.06.040","article-title":"Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model","volume":"155","author":"Feng","year":"2008","journal-title":"Neuroscience"},{"key":"B28","doi-asserted-by":"publisher","first-page":"9553","DOI":"10.3390\/ijms22179553","article-title":"A transcriptomic meta-analysis shows lipid metabolism dysregulation as an early pathological mechanism in the spinal cord of SOD1 mice","volume":"22","author":"Fernandez-Beltran","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"867","DOI":"10.3390\/biom11060867","article-title":"Diabetes mellitus and amyotrophic lateral sclerosis: a systematic review","volume":"11","author":"Ferri","year":"2021","journal-title":"Biomolecules"},{"key":"B30","doi-asserted-by":"publisher","first-page":"437","DOI":"10.3390\/genes9090437","article-title":"Network-based approaches to explore complex biological systems towards network medicine","volume":"9","author":"Fiscon","year":"2018","journal-title":"Genes (Basel)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"D87","DOI":"10.1093\/nar\/gkz1001","article-title":"JASPAR 2020: update of the open-access database of transcription factor binding profiles","volume":"48","author":"Fornes","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s10863-014-9589-1","article-title":"Evidence to support mitochondrial neuroprotection, in severe traumatic brain injury","volume":"47","author":"Gajavelli","year":"2015","journal-title":"J. Bioenerg. Biomembr."},{"key":"B33","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1111\/ene.14554","article-title":"Cardiovascular disease, psychiatric diagnosis and sex differences in the multistep hypothesis of amyotrophic lateral sclerosis","volume":"28","author":"Garton","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.brainres.2004.06.024","article-title":"Ovariectomy and 17\u03b2-estradiol modulate disease progression of a mouse model of ALS","volume":"1021","author":"Groeneveld","year":"2004","journal-title":"Brain Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"17085","DOI":"10.1038\/nrdp.2017.71","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B36","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1093\/brain\/118.3.707","article-title":"Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction","volume":"118","author":"Haverkamp","year":"1995","journal-title":"Brain"},{"key":"B37","doi-asserted-by":"publisher","first-page":"11760","DOI":"10.1073\/pnas.1917038117","article-title":"TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression","volume":"117","author":"Herzog","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B38","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1111\/nan.12148","article-title":"Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones","volume":"40","author":"Highley","year":"2014","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e201910213","DOI":"10.1083\/jcb.201910213","article-title":"TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination","volume":"220","author":"Ho","year":"2021","journal-title":"J. Cell Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1111\/neup.12466","article-title":"Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis","volume":"38","author":"Hommyo","year":"2018","journal-title":"Neuropathology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"412","DOI":"10.3390\/v10080412","article-title":"Disruption by SaCas9 Endonuclease of HERV-Kenv, a retroviral gene with oncogenic and neuropathogenic potential, inhibits molecules involved in cancer and amyotrophic lateral sclerosis","volume":"10","author":"Ibba","year":"2018","journal-title":"Viruses"},{"key":"B42","doi-asserted-by":"publisher","first-page":"181","DOI":"10.2147\/CLEP.S37505","article-title":"Risk factors for amyotrophic lateral sclerosis","volume":"7","author":"Ingre","year":"2015","journal-title":"Clin. Epidemiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1093\/protein\/gzx025","article-title":"Quercitrin and quercetin 3-\u03b2-D-glucoside as chemical chaperones for the A4V SOD1 ALS-causing mutant","volume":"30","author":"Ip","year":"2017","journal-title":"Protein Eng. Des. Sel."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.3390\/ijms17122129","article-title":"Downregulation of Homer1b\/c in SOD1 G93A models of ALS: a novel mechanism of neuroprotective effect of lithium and valproic acid","volume":"17","author":"Jiang","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1093\/hmg\/ddu587","article-title":"PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43","volume":"24","author":"Joardar","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"B46","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1111\/j.1365-2826.2011.02192.x","article-title":"Regulation of choline acetyltransferase expression by 17\u03b2-oestradiol in NSC-34 cells and in the spinal cord","volume":"23","author":"Johann","year":"2011","journal-title":"J. Neuroendocrinol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"fcaa053","DOI":"10.1093\/braincomms\/fcaa053","article-title":"Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis","volume":"2","author":"Joilin","year":"2020","journal-title":"Brain Commun."},{"key":"B48","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"D239","DOI":"10.1093\/nar\/gkx1141","article-title":"DIANA-TarBase v8: a decade-long collection of experimentally supported miRNA-gene interactions","volume":"46","author":"Karagkouni","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/s0006-8993(01)02012-1","article-title":"Intrathecal cyclosporin prolongs survival of late-stage ALS mice","volume":"894","author":"Keep","year":"2001","journal-title":"Brain Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"418765","DOI":"10.1155\/2008\/418765","article-title":"Peroxisome proliferator-activated receptor-gamma in amyotrophic lateral sclerosis and Huntington\u2019s disease","volume":"2008","author":"Kiaei","year":"2008","journal-title":"PPAR Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.expneurol.2004.10.007","article-title":"Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis","volume":"191","author":"Kiaei","year":"2005","journal-title":"Exp. Neurol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1001\/jamaneurol.2015.0910","article-title":"Diabetes mellitus, obesity and diagnosis of amyotrophic lateral sclerosis: a population-based study","volume":"72","author":"Kioumourtzoglou","year":"2015","journal-title":"JAMA Neurol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1080\/21678421.2016.1208247","article-title":"Cardiovascular disease and diagnosis of amyotrophic lateral sclerosis: a population based study","volume":"17","author":"Kioumourtzoglou","year":"2016","journal-title":"Amyotroph. Lateral Scler. Frontotemporal Degeneration"},{"key":"B55","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1093\/brain\/awq345","article-title":"Phosphatase and tensin homologue\/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis","volume":"134","author":"Kirby","year":"2011","journal-title":"Brain"},{"key":"B56","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1046\/j.1471-4159.2003.02181.x","article-title":"An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment","volume":"88","author":"Kirkinezos","year":"2004","journal-title":"J. Neurochem."},{"key":"B57","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1261\/rna.2474511","article-title":"miTALOS: analyzing the tissue-specific regulation of signaling pathways by human and mouse microRNAs","volume":"17","author":"Kowarsch","year":"2011","journal-title":"RNA"},{"key":"B58","doi-asserted-by":"publisher","first-page":"2438","DOI":"10.1093\/bioinformatics\/btq466","article-title":"ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments","volume":"26","author":"Lachmann","year":"2010","journal-title":"Bioinformatics"},{"key":"B60","doi-asserted-by":"publisher","first-page":"372","DOI":"10.3109\/17482968.2012.662988","article-title":"Reducing systemic hypermetabolism by inducing hypothyroidism does not prolong survival in the SOD1\u2013G93A mouse","volume":"13","author":"Li","year":"2012","journal-title":"Amyotroph. Lateral Scler."},{"key":"B59","doi-asserted-by":"publisher","first-page":"147234","DOI":"10.1016\/j.brainres.2020.147234","article-title":"Astrocytes in heavy metal neurotoxicity and neurodegeneration","volume":"1752","author":"Li","year":"2021","journal-title":"Brain Res."},{"key":"B61","doi-asserted-by":"publisher","first-page":"288","DOI":"10.3389\/fnmol.2018.00288","article-title":"Dysregulation of MicroRNAs and target genes networks in peripheral blood of patients with sporadic amyotrophic lateral sclerosis","volume":"11","author":"Liguori","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"B62","doi-asserted-by":"publisher","first-page":"578143","DOI":"10.3389\/fgene.2020.578143","article-title":"Key molecules and pathways underlying sporadic amyotrophic lateral sclerosis: integrated analysis on gene expression profiles of motor neurons","volume":"11","author":"Lin","year":"2020","journal-title":"Front. Genet."},{"key":"B64","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.neurobiolaging.2010.04.034","article-title":"MicroRNA-16 targets amyloid precursor protein to potentially modulate Alzheimer\u2019s-associated pathogenesis in SAMP8 mice","volume":"33","author":"Liu","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"B63","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1186\/s12974-020-01925-y","article-title":"Benzo(a)pyrene exposure induced neuronal loss, plaque deposition and cognitive decline in APP\/PS1 mice","volume":"17","author":"Liu","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"B65","article-title":"Carbamazepine","volume-title":"StatPearls [Internet]","author":"Maan","year":"2021"},{"key":"B66","doi-asserted-by":"publisher","first-page":"e1003002","DOI":"10.1371\/journal.ppat.1003002","article-title":"Early mechanisms of pathobiology are revealed by transcriptional temporal dynamics in hippocampal CA1 neurons of prion infected mice","volume":"8","author":"Majer","year":"2012","journal-title":"PLoS Pathog."},{"key":"B67","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1002\/ams2.343","article-title":"Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke","volume":"5","author":"Matsumoto","year":"2018","journal-title":"Acute Med. Surg."},{"key":"B68","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1289\/ehp.6028","article-title":"The comparative toxicogenomics database (CTD)","volume":"111","author":"Mattingly","year":"2003","journal-title":"Environ. Health Perspect."},{"key":"B69","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.genm.2010.11.010","article-title":"Effects of gender in amyotrophic lateral sclerosis","volume":"7","author":"McCombe","year":"2010","journal-title":"Gend. Med."},{"key":"B70","doi-asserted-by":"publisher","first-page":"309","DOI":"10.5114\/fn.2015.56545","article-title":"Protective effect of valproic acid on cultured motor neurons under glutamate excitotoxic conditions. ultrastructural study","volume":"53","author":"Naganska","year":"2015","journal-title":"Folia Neuropathol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"7775","DOI":"10.3390\/molecules20057775","article-title":"Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside","volume":"20","author":"Nagoshi","year":"2015","journal-title":"Molecules"},{"key":"B72","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.1097\/00001756-200011090-00019","article-title":"Protection of cultured spinal motor neurons by estradiol","volume":"11","author":"Nakamizo","year":"2000","journal-title":"Neuroreport"},{"key":"B73","doi-asserted-by":"publisher","first-page":"e100405","DOI":"10.1371\/journal.pone.0100405","article-title":"STAT3 modulation to enhance motor neuron differentiation in human neural stem cells","volume":"9","author":"Natarajan","year":"2014","journal-title":"PLoS One"},{"key":"B74","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1159\/000446850","article-title":"Cyclosporine A, a potential therapy of ischemic reperfusion injury. A common history for heart and brain","volume":"42","author":"Nighoghossian","year":"2016","journal-title":"Cerebrovasc. Dis."},{"key":"B75","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1111\/ejn.13650","article-title":"Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1(G93A) mouse model of amyotrophic lateral sclerosis","volume":"46","author":"Ohgomori","year":"2017","journal-title":"Eur. J. Neurosci."},{"key":"B76","doi-asserted-by":"publisher","first-page":"3216","DOI":"10.3390\/ijms22063216","article-title":"An integrative transcriptome-wide analysis of amyotrophic lateral sclerosis for the identification of potential genetic markers and drug candidates","volume":"22","author":"Park","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B77","doi-asserted-by":"publisher","first-page":"109820","DOI":"10.1016\/j.envres.2020.109820","article-title":"CSF neurotoxic metals\/metalloids levels in amyotrophic lateral sclerosis patients: comparison between bulbar and spinal onset","volume":"188","author":"Patti","year":"2020","journal-title":"Environ. Res."},{"key":"B78","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.neuro.2016.03.022","article-title":"Blood levels of trace metals and amyotrophic lateral sclerosis","volume":"54","author":"Peters","year":"2016","journal-title":"Neurotoxicology"},{"key":"B79","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1002\/ana.21620","article-title":"Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis","volume":"66","author":"Piepers","year":"2009","journal-title":"Ann. Neurol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"e0222921","DOI":"10.1371\/journal.pone.0222921","article-title":"Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer\u2019s patients","volume":"14","author":"Potashkin","year":"2019","journal-title":"PLoS One"},{"key":"B81","doi-asserted-by":"publisher","first-page":"3787","DOI":"10.3390\/ijms21113787","article-title":"Bioinformatic analysis reveals phosphodiesterase 4D-interacting protein as a key frontal cortex dementia switch gene","volume":"21","author":"Potashkin","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B82","doi-asserted-by":"publisher","first-page":"104814","DOI":"10.1016\/j.neuint.2020.104814","article-title":"Minutes of PPAR-gamma agonism and neuroprotection","volume":"140","author":"Prashantha Kumar","year":"2020","journal-title":"Neurochem. Int."},{"key":"B83","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/s41591-018-0304-3","article-title":"Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer\u2019s disease","volume":"25","author":"Preische","year":"2019","journal-title":"Nat. Med."},{"key":"B84","doi-asserted-by":"publisher","first-page":"e0151771","DOI":"10.1371\/journal.pone.0151771","article-title":"miTALOS v2: analyzing tissue specific microRNA function","volume":"11","author":"Preusse","year":"2016","journal-title":"PLoS One"},{"key":"B85","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1080\/17482960802163614","article-title":"Medications and laboratory parameters as prognostic factors in amyotrophic lateral sclerosis","volume":"9","author":"Qureshi","year":"2008","journal-title":"Amyotroph. Lateral Scler."},{"key":"B86","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.compbiolchem.2018.12.011","article-title":"Network-based approach to identify molecular signatures and therapeutic agents in Alzheimer\u2019s disease","volume":"78","author":"Rahman","year":"2019","journal-title":"Comput. Biol. Chem."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1016\/j.ygeno.2019.07.018","article-title":"Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer\u2019s disease: insights from a systems biomedicine perspective","volume":"112","author":"Rahman","year":"2020","journal-title":"Genomics"},{"key":"B88","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.lfs.2017.06.009","article-title":"Gene networks in neurodegenerative disorders","volume":"183","author":"Recabarren","year":"2017","journal-title":"Life Sci."},{"key":"B89","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.lfs.2017.12.016","article-title":"New insights into the gene expression associated to amyotrophic lateral sclerosis","volume":"193","author":"Recabarren-Leiva","year":"2018","journal-title":"Life Sci."},{"key":"B90","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.bcp.2018.07.049","article-title":"Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1(G93A) transgenic mice, an experimental model of amyotrophic lateral sclerosis","volume":"157","author":"Rodriguez-Cueto","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"5535","DOI":"10.1523\/JNEUROSCI.1139-07.2007","article-title":"Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model","volume":"27","author":"Rouaux","year":"2007","journal-title":"J. Neurosci."},{"key":"B92","doi-asserted-by":"publisher","first-page":"7150","DOI":"10.3390\/ijms22137150","article-title":"Network analysis identifies sex-specific gene expression changes in blood of amyotrophic lateral sclerosis patients","volume":"22","author":"Santiago","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.3390\/genes12121946","article-title":"Machine learning and bioinformatics framework integration to potential familial DCM-related markers discovery","volume":"12","author":"Schiano","year":"2021","journal-title":"Genes (Basel)"},{"key":"B94","doi-asserted-by":"publisher","first-page":"e9002","DOI":"10.1371\/journal.pone.0009002","article-title":"A neurotoxic phosphoform of Elk-1 associates with inclusions from multiple neurodegenerative diseases","volume":"5","author":"Sharma","year":"2010","journal-title":"PLoS One"},{"key":"B95","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.neuroscience.2016.02.055","article-title":"Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus","volume":"324","author":"Sharma","year":"2016","journal-title":"Neuroscience"},{"key":"B96","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1161\/STROKEAHA.118.023436","article-title":"Epigenome-wide association study indicates hypomethylation of MTRNR2L8 in large-artery atherosclerosis stroke","volume":"50","author":"Shen","year":"2019","journal-title":"Stroke"},{"key":"B97","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1159\/000213762","article-title":"Activation of signal transducer and activator of transcription-3 in the spinal cord of sporadic amyotrophic lateral sclerosis patients","volume":"6","author":"Shibata","year":"2009","journal-title":"Neurodegener. Dis."},{"key":"B98","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1111\/j.1440-1789.2009.01078.x","article-title":"Activation of STAT3 and inhibitory effects of pioglitazone on STAT3 activity in a mouse model of SOD1-mutated amyotrophic lateral sclerosis","volume":"30","author":"Shibata","year":"2010","journal-title":"Neuropathology"},{"key":"B99","doi-asserted-by":"publisher","first-page":"3179","DOI":"10.1111\/j.1460-9568.2004.03765.x","article-title":"Benefit of valproic acid in suppressing disease progression of ALS model mice","volume":"20","author":"Sugai","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"B100","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/s12876-015-0342-y","article-title":"Altered intestinal functions and increased local inflammation in insulin-resistant obese subjects: a gene-expression profile analysis","volume":"15","author":"Veilleux","year":"2015","journal-title":"BMC Gastroenterol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"752","DOI":"10.7150\/ijbs.11880","article-title":"Valproate attenuates 25-kDa C-terminal fragment of TDP-43-induced neuronal toxicity via suppressing endoplasmic reticulum stress and activating autophagy","volume":"11","author":"Wang","year":"","journal-title":"Int. J. Biol. Sci."},{"key":"B102","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.neuroscience.2015.06.002","article-title":"Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate","volume":"301","author":"Wang","year":"","journal-title":"Neuroscience"},{"key":"B101","doi-asserted-by":"publisher","first-page":"2502","DOI":"10.1038\/nprot.2013.150","article-title":"Target analysis by integration of transcriptome and ChIP-seq data with BETA","volume":"8","author":"Wang","year":"2013","journal-title":"Nat. Protoc."},{"key":"B104","doi-asserted-by":"publisher","first-page":"106248","DOI":"10.1016\/j.clineuro.2020.106248","article-title":"Diabetes mellitus is associated with a lower risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis","volume":"199","author":"Wannarong","year":"2020","journal-title":"Clin. Neurol. Neurosurg."},{"key":"B106","doi-asserted-by":"publisher","first-page":"106033","DOI":"10.1016\/j.jstrokecerebrovasdis.2021.106033","article-title":"Epigenetics modifications in large-artery atherosclerosis: a systematic review","volume":"30","author":"Wong","year":"2021","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"B105","doi-asserted-by":"publisher","first-page":"2799","DOI":"10.1093\/hmg\/ddz104","article-title":"Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes","volume":"28","author":"Wong","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"B107","doi-asserted-by":"publisher","first-page":"115658","DOI":"10.1016\/j.taap.2021.115658","article-title":"Benzo(a)pyrene exposure in utero exacerbates Parkinson\u2019s Disease (PD)-like \u03b1-synucleinopathy in A53T human \u03b1-synuclein transgenic mice","volume":"427","author":"Xu","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"4345","DOI":"10.1093\/hmg\/ddu152","article-title":"Distinct pathways leading to TDP-43-induced cellular dysfunctions","volume":"23","author":"Yamashita","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"B109","doi-asserted-by":"publisher","first-page":"113414","DOI":"10.1016\/j.expneurol.2020.113414","article-title":"Elevated exosomal secretion of miR-124-3p from spinal neurons positively associates with disease severity in ALS","volume":"333","author":"Yelick","year":"2020","journal-title":"Exp. Neurol."},{"key":"B110","doi-asserted-by":"publisher","first-page":"24840","DOI":"10.1073\/pnas.1908113116","article-title":"Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington\u2019s disease","volume":"116","author":"Yildirim","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B111","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.mcn.2015.08.009","article-title":"Downregulated AEG-1 together with inhibited PI3K\/Akt pathway is associated with reduced viability of motor neurons in an ALS model","volume":"68","author":"Yin","year":"2015","journal-title":"Mol. Cell Neurosci."},{"key":"B112","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1111\/cns.12855","article-title":"Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1\u2013G93A mouse model","volume":"24","author":"Zhang","year":"2018","journal-title":"CNS Neurosci. Ther."},{"key":"B113","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1007\/s10072-014-1658-z","article-title":"An exploratory study of the association between thyroid hormone and survival of amyotrophic lateral sclerosis","volume":"35","author":"Zheng","year":"2014","journal-title":"Neurol. Sci."},{"key":"B114","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.brainresbull.2018.05.017","article-title":"Raloxifene, a promising estrogen replacement, limits TDP-25 cell death by enhancing autophagy and suppressing apoptosis","volume":"140","author":"Zhou","year":"2018","journal-title":"Brain Res. Bull."},{"key":"B115","doi-asserted-by":"publisher","first-page":"W234","DOI":"10.1093\/nar\/gkz240","article-title":"NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis","volume":"47","author":"Zhou","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B116","doi-asserted-by":"publisher","first-page":"113132","DOI":"10.1016\/j.ecoenv.2021.113132","article-title":"Risk of neurodegeneration among residents of electronic waste recycling areas","volume":"230","author":"Zhu","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.825031\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T09:33:49Z","timestamp":1647336829000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.825031\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,15]]},"references-count":116,"alternative-id":["10.3389\/fnmol.2022.825031"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2022.825031","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,15]]},"article-number":"825031"}}