{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:16:57Z","timestamp":1787062617296,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T00:00:00Z","timestamp":1587340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20 GM103650"],"award-info":[{"award-number":["P20 GM103650"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.<\/jats:p>","DOI":"10.3390\/genes11040448","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T05:48:52Z","timestamp":1587448132000},"page":"448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS"],"prefix":"10.3390","volume":"11","author":[{"given":"Aayan N.","family":"Patel","sequence":"first","affiliation":[{"name":"Davidson Academy, Reno, NV 89503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2096-6334","authenticated-orcid":false,"given":"Dennis","family":"Mathew","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Nevada, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.4103\/2152-7806.169561","article-title":"A comprehensive review of amyotrophic lateral sclerosis","volume":"6","author":"Zarei","year":"2015","journal-title":"Surg. Neurol. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1093\/brain\/awr366","article-title":"Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72","volume":"135","author":"Chio","year":"2012","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/ng0595-61","article-title":"Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase","volume":"10","author":"Andersen","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","article-title":"TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"351","author":"Arai","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","first-page":"252","article-title":"Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis","volume":"30","author":"Volk","year":"2018","journal-title":"Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1089\/ars.2009.2444","article-title":"Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis","volume":"11","author":"Foran","year":"2009","journal-title":"Antioxid. Redox Sign."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1056\/NEJM199205283262204","article-title":"Decreased Glutamate Transport by the Brain and Spinal-Cord in Amyotrophic-Lateral-Sclerosis","volume":"326","author":"Rothstein","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1074\/jbc.M003779200","article-title":"Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity","volume":"276","author":"Trotti","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.nbd.2011.12.033","article-title":"Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons","volume":"45","author":"Hideyama","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0022-510X(01)00661-X","article-title":"Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: A reappraisal using a new HPLC method with coulometric detection in a large cohort of patients","volume":"193","author":"Bensimon","year":"2002","journal-title":"J. Neurol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1124\/mol.53.4.742","article-title":"Reverse Na+\/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons","volume":"53","author":"Hoyt","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.nbd.2011.12.051","article-title":"Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+\/Ca2+ exchanger","volume":"46","author":"Brittain","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neuron.2013.12.009","article-title":"Neuronal Matrix Metalloproteinase-9 is a Determinant of Selective Neurodegeneration","volume":"81","author":"Kaplan","year":"2014","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00401-017-1708-8","article-title":"Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis","volume":"133","author":"Nijssen","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nizzardo, M., Taiana, M., Rizzo, F., Aguila Benitez, J., Nijssen, J., Allodi, I., Melzi, V., Bresolin, N., Comi, G.P., and Hedlund, E. (2020). Synaptotagmin 13 is neuroprotective across motor neuron diseases. Acta Neuropathol.","DOI":"10.1007\/s00401-020-02133-x"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"25960","DOI":"10.1038\/srep25960","article-title":"Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS","volume":"6","author":"Allodi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liu, X.T., Chen, J.H., Guan, T.Y., Yao, H., Zhang, W.P., Guan, Z.L., and Wang, Y.Q. (2019). miRNAs and target genes in the blood as biomarkers for the early diagnosis of Parkinson\u2019s disease. BMC Syst. Biol., 13.","DOI":"10.1186\/s12918-019-0680-4"},{"key":"ref_18","first-page":"4810","article-title":"Identification and bioinformatics analysis of overlapping differentially expressed genes in depression, papillary thyroid cancer and uterine fibroids","volume":"15","author":"Tang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene expression omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","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. Genom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s00401-012-1058-5","article-title":"Unravelling the enigma of selective vulnerability in neurodegeneration: Motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity","volume":"125","author":"Brockington","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1528-1167.2008.01841.x","article-title":"Ketosis and brain handling of glutamate, glutamine, and GABA","volume":"49","author":"Yudkoff","year":"2008","journal-title":"Epilepsia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fnmol.2019.00025","article-title":"Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis","volume":"12","author":"Prasad","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1038\/s41598-018-19802-3","article-title":"Downregulation of glutamic acid decarboxylase in Drosophila TDP-43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses","volume":"8","author":"Romano","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40224","DOI":"10.1074\/jbc.R112.386664","article-title":"Structure, Function, and Modulation of GABA(A) Receptors","volume":"287","author":"Sigel","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1124\/mol.55.1.168","article-title":"Spontaneous and gamma-aminobutyric acid (GABA)-activated GABA(A) receptor channels formed by epsilon subunit-containing isoforms","volume":"55","author":"Neelands","year":"1999","journal-title":"Mol. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0014-2999(03)02125-3","article-title":"Pharmacology of GABA(A) receptors exhibiting different levels of spontaneous activity","volume":"476","author":"Mortensen","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fnmol.2012.00025","article-title":"Three functional facets of calbindin D-28k","volume":"5","author":"Schmidt","year":"2012","journal-title":"Front. Mol. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ceca.2009.12.002","article-title":"Calcium dysregulation in amyotrophic lateral sclerosis","volume":"47","author":"Grosskreutz","year":"2010","journal-title":"Cell Calcium"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.bbrc.2016.08.089","article-title":"Calcium in the pathomechanism of amyotrophic lateral sclerosis\u2014Taking center stage?","volume":"483","author":"Patai","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/ana.410360608","article-title":"The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic-lateral-sclerosis","volume":"36","author":"Alexianu","year":"1994","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1113\/jphysiol.2011.226985","article-title":"Glutamate modulates the firing rate in oculomotor nucleus motoneurons as a function of the recruitment threshold current","volume":"590","author":"Carrascal","year":"2012","journal-title":"J. Physiol. Lond."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1111\/j.1460-9568.2008.06436.x","article-title":"GABA(A) receptors present higher affinity and modified subunit composition in spinal motor neurons from a genetic model of amyotrophic lateral sclerosis","volume":"28","author":"Carunchio","year":"2008","journal-title":"Eur. J. Neurosci."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/4\/448\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:09:04Z","timestamp":1760364544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/4\/448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,20]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["genes11040448"],"URL":"https:\/\/doi.org\/10.3390\/genes11040448","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,20]]}}}