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However, the mechanisms underlying the selective vulnerability of motor neurons and the involvement of non-motor neuron cells in ALS remain unclear.<\/jats:p>\n                  <jats:p>To investigate ALS pathology at the cellular level, we performed a single-nucleus multiome analysis, including RNA sequencing and chromatin accessibility profiling, on the motor cortex (75 583 nuclei) and spinal cord (62 711 nuclei) from patients with ALS (n = 6) and controls (n = 6).<\/jats:p>\n                  <jats:p>Our results revealed significant gene expression changes specifically in spinal motor neurons, including upregulation of a metabotropic glutamate receptor, GRM5, and enhanced glutamate signalling. By integrating genome-wide association study data, we identified ALS-associated single nucleotide polymorphisms (SNPs) in regulatory regions, suggesting cell-type-specific enrichment of risk, especially in microglia.<\/jats:p>\n                  <jats:p>These findings suggest that changes in spinal motor neurons and their surrounding environment, including glutamate signalling, may be involved in ALS pathology. The study also provides valuable resources for future research on the underlying mechanisms and potential therapeutic targets.<\/jats:p>","DOI":"10.1093\/brain\/awaf426","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T18:35:15Z","timestamp":1762886115000},"page":"2480-2494","source":"Crossref","is-referenced-by-count":8,"title":["Single-nucleus multiome shows motor neuron glutamate overactivation in amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"149","author":[{"given":"Eriko","family":"Takeuchi","sequence":"first","affiliation":[{"name":"Department of Neurology, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Neurotherapeutics, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9872-4909","authenticated-orcid":false,"given":"Yoshiaki","family":"Yasumizu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Experimental Immunology, Immunology Frontier Research Center, The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT 06510 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565-0871 ,","place":["Japan"]},{"name":"Department of Genomic Medicine, National Cerebral and Cardiovascular Center , Suita, Osaka 564-8565 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine (IRUD Analysis Center), The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Genomic Medicine, National Cerebral and Cardiovascular Center , Suita, Osaka 564-8565 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohji","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Morii","sequence":"additional","affiliation":[{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Pathology, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goichi","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Neuropathology (Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology , Itabashi, Tokyo 173-0015 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Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center , Toyonaka, Osaka 560-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiichi","family":"Nagano","sequence":"additional","affiliation":[{"name":"Department of Neurology, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Neurotherapeutics, The University of Osaka Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Neurodevelopmental and Neurodegenerative Disease Research, The University of Osaka United Graduate School of Child Development , Suita, Osaka 565-0871 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