{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:51:39Z","timestamp":1791075099859,"version":"4.1.0"},"reference-count":213,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K07508"],"award-info":[{"award-number":["JP22K07508"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Committee of Ataxia, Health Labor Sciences Research Grant, Ministry of Health, Labor and Welfare, Japan","award":["JPMH20FC1041"],"award-info":[{"award-number":["JPMH20FC1041"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["22dk0207055h0002"],"award-info":[{"award-number":["22dk0207055h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21wm0425016"],"award-info":[{"award-number":["JP21wm0425016"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The core pathological event in Parkinson\u2019s disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.<\/jats:p>","DOI":"10.3390\/ijms25042009","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T03:47:09Z","timestamp":1707277629000},"page":"2009","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Parkinson\u2019s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-8536","authenticated-orcid":false,"given":"Hirohisa","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Neurology, School of Medicine, Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes M.","family":"Dijkstra","sequence":"additional","affiliation":[{"name":"Center for Medical Science, Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9216-6029","authenticated-orcid":false,"given":"Toshiharu","family":"Nagatsu","sequence":"additional","affiliation":[{"name":"Center for Research Promotion and Support, Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1002\/mds.25844","article-title":"Time to Redefine PD? 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