{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:12:46Z","timestamp":1790374366090,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T00:00:00Z","timestamp":1695859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ROCHE Pharma AG"},{"name":"Medical Faculty of the University of Duisburg-Essen, Germany"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>5q-related Spinal muscular atrophy (SMA) is a hereditary multi-systemic disorder leading to progressive muscle atrophy and weakness caused by the degeneration of spinal motor neurons (MNs) in the ventral horn of the spinal cord. Three SMN-enhancing drugs for SMA treatment are available. However, even if these drugs are highly effective when administrated early, several patients do not benefit sufficiently or remain non-responders, e.g., adults suffering from late-onset SMA and starting their therapy at advanced disease stages characterized by long-standing irreversible loss of MNs. Therefore, it is important to identify additional molecular targets to expand therapeutic strategies for SMA treatment and establish prognostic biomarkers related to the treatment response. Using high-throughput nCounter NanoString technology, we analyzed serum samples of late-onset SMA type 2 and type 3 patients before and six months under nusinersen treatment. Four genes (AMIGO1, CA2, CCL5, TLR2) were significantly altered in their transcript counts in the serum of patients, where differential expression patterns were dependent on SMA subtype and treatment response, assessed with outcome scales. No changes in gene expression were observed six months after nusinersen treatment, compared to healthy controls. These alterations in the transcription of four genes in SMA patients qualified those genes as potential SMN-independent therapeutic targets to complement current SMN-enhancing therapies.<\/jats:p>","DOI":"10.3390\/cells12192374","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T05:55:54Z","timestamp":1695880554000},"page":"2374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Analysis of Free Circulating Messenger Ribonucleic Acids in Serum Samples from Late-Onset Spinal Muscular Atrophy Patients Using nCounter NanoString Technology"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3449-9829","authenticated-orcid":false,"given":"Markus","family":"Leo","sequence":"first","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda-Isabell","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1067-0051","authenticated-orcid":false,"given":"Fabian","family":"Mairinger","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2833-0928","authenticated-orcid":false,"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Center for Neuromuscular Disorders, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Hansmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Hezel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8509-6563","authenticated-orcid":false,"given":"Jelena","family":"Skuljec","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Refik","family":"Pul","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Schara-Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Center for Neuromuscular Disorders, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1650-8875","authenticated-orcid":false,"given":"Christoph","family":"Kleinschnitz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3631-3450","authenticated-orcid":false,"given":"Tim","family":"Hagenacker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1016\/S0140-6736(08)60921-6","article-title":"Spinal muscular atrophy","volume":"371","author":"Lunn","year":"2008","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/ng0797-265","article-title":"Correlation between severity and SMN protein level in spinal muscular atrophy","volume":"16","author":"Lefebvre","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s00401-023-02554-4","article-title":"Spinal astrocyte dysfunction drives motor neuron loss in late-onset spinal muscular atrophy","volume":"145","author":"Schmitt","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1002\/glia.22522","article-title":"Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production","volume":"61","author":"McGivern","year":"2013","journal-title":"Glia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1002\/glia.24340","article-title":"Diminished motor neuron activity driven by abnormal astrocytic EAAT1 glutamate transporter activity in spinal muscular atrophy is not fully restored after lentiviral SMN delivery","volume":"71","author":"Welby","year":"2023","journal-title":"Glia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12943-022-01543-7","article-title":"Liquid biopsy: A step closer to transform diagnosis, prognosis and future of cancer treatments","volume":"21","author":"Lone","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sorber, L., Zwaenepoel, K., Jacobs, J., De Winne, K., Goethals, S., Reclusa, P., Van Casteren, K., Augustus, E., Lardon, F., and Roeyen, G. (2019). Circulating Cell-Free DNA and RNA Analysis as Liquid Biopsy: Optimal Centrifugation Protocol. Cancers, 11.","DOI":"10.3390\/cancers11040458"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bruno, D.C.F., Donatti, A., Martin, M., Almeida, V.S., Geraldis, J.C., Oliveira, F.S., Dogini, D.B., and Lopes-Cendes, I. (2020). Circulating nucleic acids in the plasma and serum as potential biomarkers in neurological disorders. Braz. J. Med. Biol. Res., 53.","DOI":"10.1590\/1414-431x20209881"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"925","DOI":"10.18632\/aging.100624","article-title":"Plasma microRNA biomarkers for detection of mild cognitive impairment: Biomarker validation study","volume":"5","author":"Sheinerman","year":"2013","journal-title":"Aging"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ravnik-Glavac, M., and Glavac, D. (2020). Circulating RNAs as Potential Biomarkers in Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051714"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9571","DOI":"10.2147\/CMAR.S219872","article-title":"Digital Immune-Related Gene Expression Signatures In High-Grade Serous Ovarian Carcinoma: Developing Prediction Models For Platinum Response","volume":"11","author":"Mairinger","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1138625","DOI":"10.3389\/fgene.2023.1138625","article-title":"Integrated analysis of circulating cell free nucleic acids for cancer genotyping and immune phenotyping of tumor microenvironment","volume":"14","author":"Chaddha","year":"2023","journal-title":"Front. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1080\/14737159.2019.1633307","article-title":"The potential of circulating cell free RNA as a biomarker in cancer","volume":"19","author":"Cheung","year":"2019","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/s41431-018-0132-4","article-title":"Circulating cell-free nucleic acids: Characteristics and applications","volume":"26","author":"Pos","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1021\/bi9526692","article-title":"Reversal of the hydrogen bond to zinc ligand histidine-119 dramatically diminishes catalysis and enhances metal equilibration kinetics in carbonic anhydrase II","volume":"35","author":"Huang","year":"1996","journal-title":"Biochemistry"},{"key":"ref_17","first-page":"175","article-title":"The catalytic mechanism of mammalian carbonic anhydrases","volume":"90","author":"Lindskog","year":"2000","journal-title":"EXS"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev.bi.64.070195.002111","article-title":"Human carbonic anhydrases and carbonic anhydrase deficiencies","volume":"64","author":"Sly","year":"1995","journal-title":"Annu. Rev. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0009-8981(83)90405-9","article-title":"Carbonic anhydrase III in Duchenne muscular dystrophy","volume":"133","author":"Carter","year":"1983","journal-title":"Clin. Chim. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1093\/clinchem\/37.1.36","article-title":"Carbonic anhydrase III in serum in muscular dystrophy and other neurological disorders: Relationship with creatine kinase","volume":"37","author":"Ohta","year":"1991","journal-title":"Clin. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1001\/archneur.1988.00520350092022","article-title":"Muscle-specific carbonic anhydrase III is a more sensitive marker of muscle damage than creatine kinase in neuromuscular disorders","volume":"45","author":"Vaananen","year":"1988","journal-title":"Arch. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/0022-510X(85)90118-2","article-title":"Serum carbonic anhydrase III in progressive muscular dystrophy","volume":"67","author":"Mokuno","year":"1985","journal-title":"J. Neurol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3389\/fnana.2017.00137","article-title":"Glial- and Neuronal-Specific Expression of CCL5 mRNA in the Rat Brain","volume":"11","author":"Lanfranco","year":"2017","journal-title":"Front. Neuroanat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1002\/glia.21035","article-title":"Morphine induces the release of CCL5 from astrocytes: Potential neuroprotective mechanism against the HIV protein gp120","volume":"58","author":"Avdoshina","year":"2010","journal-title":"Glia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1523\/JNEUROSCI.4689-06.2007","article-title":"Interferon-gamma-oligodendrocyte interactions in the regulation of experimental autoimmune encephalomyelitis","volume":"27","author":"Balabanov","year":"2007","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1517\/14728222.2013.837886","article-title":"Targeting CCL5 in inflammation","volume":"17","author":"Marques","year":"2013","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1146\/annurev.cellbio.21.122303.115827","article-title":"Recognition and signaling by toll-like receptors","volume":"22","author":"West","year":"2006","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.imbio.2008.02.005","article-title":"TLR2\u2014Promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity","volume":"213","author":"Zahringer","year":"2008","journal-title":"Immunobiology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"427473","DOI":"10.1155\/2011\/427473","article-title":"Surface TLR2 and TLR4 expression on mature rat mast cells can be affected by some bacterial components and proinflammatory cytokines","volume":"2011","author":"Pietrzak","year":"2011","journal-title":"Mediat. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1523\/JNEUROSCI.1164-21.2022","article-title":"AMIGO1 Promotes Axon Growth and Territory Matching in the Retina","volume":"42","author":"Soto","year":"2022","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/j.bpj.2022.03.020","article-title":"The AMIGO1 adhesion protein activates Kv2.1 voltage sensors","volume":"121","author":"Sepela","year":"2022","journal-title":"Biophys. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/embor.2011.204","article-title":"AMIGO is an auxiliary subunit of the Kv2.1 potassium channel","volume":"12","author":"Peltola","year":"2011","journal-title":"EMBO Rep."},{"key":"ref_34","first-page":"191","article-title":"AMIGO-Kv2.1 Potassium Channel Complex Is Associated With Schizophrenia-Related Phenotypes","volume":"42","author":"Peltola","year":"2016","journal-title":"Schizophr. Bull."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"jcs256339","DOI":"10.1242\/jcs.256339","article-title":"Kv2 channel-AMIGO beta-subunit assembly modulates both channel function and cell adhesion molecule surface trafficking","volume":"134","author":"Maverick","year":"2021","journal-title":"J. Cell. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"19958","DOI":"10.1074\/jbc.M113.545582","article-title":"Amigo adhesion protein regulates development of neural circuits in zebrafish brain","volume":"289","author":"Zhao","year":"2014","journal-title":"J. Biol. Chem"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Millino, C., Fanin, M., Vettori, A., Laveder, P., Mostacciuolo, M.L., Angelini, C., and Lanfranchi, G. (2009). Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy. BMC Med., 7.","DOI":"10.1186\/1741-7015-7-14"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1093\/brain\/awg208","article-title":"Protein expression changes in spinal muscular atrophy revealed with a novel antibody array technology","volume":"126","author":"Anderson","year":"2003","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1182\/blood-2010-08-265892","article-title":"Cytokine release from innate immune cells: Association with diverse membrane trafficking pathways","volume":"118","author":"Lacy","year":"2011","journal-title":"Blood"},{"key":"ref_40","first-page":"79","article-title":"The Role of TLR2 in Infection and Immunity","volume":"3","author":"Massari","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.4049\/jimmunol.2100665","article-title":"Carbon Dioxide Sensing by Immune Cells Occurs through Carbonic Anhydrase 2-Dependent Changes in Intracellular pH","volume":"208","author":"Strowitzki","year":"2022","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1528-1157.2000.tb02169.x","article-title":"Topiramate as an inhibitor of carbonic anhydrase isoenzymes","volume":"41","author":"Dodgson","year":"2000","journal-title":"Epilepsia"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/19\/2374\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:00:30Z","timestamp":1760130030000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/19\/2374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,28]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["cells12192374"],"URL":"https:\/\/doi.org\/10.3390\/cells12192374","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,28]]}}}