{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:21:52Z","timestamp":1788520912129,"version":"build-2803163510"},"reference-count":62,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Oberlin College Arts and Sciences Dean\u2019s Office","award":["Research and Professional Development Portfolio"],"award-info":[{"award-number":["Research and Professional Development Portfolio"]}]},{"name":"Robert W. &amp; Eleanor H. Biggs Endowed Professor of Neuroscience","award":["Endowed Professor Research Portfolio"],"award-info":[{"award-number":["Endowed Professor Research Portfolio"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>There are no disease-modifying treatments available for Huntington\u2019s disease (HD), a neurodegenerative disease caused by a genetic mutation in the Huntingtin gene. Previous research suggests that disruptions in the bioenergetics of the mitochondria and increased oxidative stress are potential inducers of HD. Therapies that enhance antioxidant pathways intend to target and attenuate the overproduction of reactive oxygen species associated with mitochondrial dysfunction. We have investigated the effect of Methylene Blue (MB) as a potential therapy for HD. MB is a small molecule demonstrated to exhibit neuroprotective effects in other neurodegenerative disease models, including Parkinson\u2019s and Alzheimer\u2019s, by attenuating the oxidative stress pathways implicated in their pathophysiology. We used an established striatal cell model of HD expressing wild-type (STHdhQ7\/Q7) or mutant (STHdhQ111\/Q111) HTT and a chemical inducer of HD, 3-Nitropropionic acid (3-NPA), to determine the HD-specific mechanisms regulated by 3 h of MB pre-treatment. Upon 24 h of exposure to 3-NPA, mutant HD cells exhibited a significant concentration-dependent decrease in cell survival and a concomitant increase in cell death compared to wild-type, confirming that 3-NPA exacerbates mutant HTT neurotoxicity. Examination of mitochondrial membrane potential and mitochondrial function in the striatal cells by JC-1 and ATP assays, respectively, revealed MB mediated neuroprotection against 3-NPA-induced reduction in mitochondrial activity. Immunoblotting analysis revealed that MB restores baseline expression of oxidative-stress-related proteins, including HO1 and p62, in both wild-type and mutant cells exposed to 3-NPA. Our findings establish a novel neuroprotective role of MB in both genetic and pharmacological models of HD, suggesting that MB might be a promising therapeutic candidate for altering the underlying pathophysiology of HD by improving mitochondrial function.<\/jats:p>","DOI":"10.3390\/ijms262110672","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:15:14Z","timestamp":1762175714000},"page":"10672","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Methylene Blue Attenuates 3-Nitropropionic Acid-Induced Oxidative Stress and Mitochondrial Dysfunction in Striatal Cells: Therapeutic Implications in Huntington\u2019s Disease Neuropathology"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7344-3099","authenticated-orcid":false,"given":"Hannah K.","family":"Hale","sequence":"first","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5502-813X","authenticated-orcid":false,"given":"Kayla M.","family":"Elias","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Ho","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9486-2044","authenticated-orcid":false,"given":"Gunnar F.","family":"Kwakye","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-71779-1_1","article-title":"Clinical Features of Huntington\u2019s Disease","volume":"1049","author":"Ghosh","year":"2018","journal-title":"Adv. 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