{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:20:46Z","timestamp":1790709646946,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["22K11403"],"award-info":[{"award-number":["22K11403"]}]},{"DOI":"10.13039\/501100001691","name":"Ministry of Education, Culture, Sports, Science, and Technology (MEXT)","doi-asserted-by":"publisher","award":["22K11403"],"award-info":[{"award-number":["22K11403"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of the Environment (MOE)","award":["22K11403"],"award-info":[{"award-number":["22K11403"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sensory disturbances and central nervous system symptoms are important in patients with Minamata disease. In the peripheral nervous system of these patients, motor nerves are not strongly injured, whereas sensory nerves are predominantly affected. In this study, we investigated the mechanisms underlying the sensory-predominant impairment of the peripheral nervous system caused by methylmercury. We found that the types of cell death in rat dorsal root ganglion (DRG) neurons caused by methylmercury included apoptosis, necrosis, and necroptosis. Methylmercury induced apoptosis in cultured rat DRG neurons but not in anterior horn neurons or Schwann cells. Additionally, methylmercury activated both caspase 8 and caspase 3 in DRG neurons. It increased the expression of tumor necrosis factor (TNF) receptor-1 and the phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL). The expression of TNF-\u03b1 was increased in macrophage-like RAW264.7 cells by methylmercury. The increase was suggested to be mediated by the NF-\u03baB pathway. Moreover, methylmercury induced neurological symptoms, evaluated by a hindlimb extension response, were significantly less severe in TNF-\u03b1 knockout mice. Based on these results and our previous studies, we propose the following hypothesis regarding the pathogenesis of sensory nerve-predominant damage by methylmercury: First, methylmercury accumulates within sensory nerve neurons and initiates cell death mechanisms, such as apoptosis, on a small scale. Second, cell death triggers the infiltration of macrophages into the sensory fibers. Third, the macrophages are stimulated by methylmercury and secrete TNF-\u03b1 through the NF-\u03baB pathway. Fourth, TNF-\u03b1 induces cell death mechanisms, including necrosis, apoptosis through the caspase 8\/3 pathway, and necroptosis through the TNFR1-RIP1-RIP3-MLKL pathway, activated by methylmercury in sensory neurons. Consequently, methylmercury exhibits potent cytotoxicity specific to the DRG\/sensory nerve cells in the peripheral nervous system. This chain of events caused by methylmercury may contribute to sensory disturbances in patients with Minamata disease.<\/jats:p>","DOI":"10.3390\/ijms252111672","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T09:11:24Z","timestamp":1730279484000},"page":"11672","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mechanisms Underlying Sensory Nerve-Predominant Damage by Methylmercury in the Peripheral Nervous System"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3582-7780","authenticated-orcid":false,"given":"Tsuyoshi","family":"Nakano","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, Japan"},{"name":"Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5957-7697","authenticated-orcid":false,"given":"Eiko","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, Japan"},{"name":"Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, 1646 Abiko, Abiko 270-1194, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigekatsu","family":"Kazama","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0028-0658","authenticated-orcid":false,"given":"Yasuyuki","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komyo","family":"Eto","sequence":"additional","affiliation":[{"name":"Health and Nursing Facilities for the Aged, Jushindai, Shinwakai, 272 Ikurakitakata, Tamana 865-0041, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9934-5775","authenticated-orcid":false,"given":"Yoichiro","family":"Iwakura","sequence":"additional","affiliation":[{"name":"Research Institute for Biomedical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, 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