{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:21:05Z","timestamp":1791865265824,"version":"4.3.4"},"reference-count":479,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CHDI Foundation, Freemasons New Zealand, and New Zealand Ministry of Business Innovation and Employment funding for New Zealand\u2013China Non-Communicable Diseases Research","award":["UOOX1601"],"award-info":[{"award-number":["UOOX1601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as a highly penetrant dominant disorder likely acting through a toxic gain of function by the mutant huntingtin protein. Widespread cellular degeneration of the medium spiny neurons of the caudate nucleus and putamen are responsible for the onset of symptomology that encompasses motor, cognitive, and behavioural abnormalities. Over the past 150 years of HD research since George Huntington published his description, a plethora of pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption of proteostasis, transcriptional dysregulation, and neuroinflammation. Despite the identification and characterisation of the causative gene and mutation and significant advances in our understanding of the cellular pathology in recent years, a disease-modifying intervention has not yet been clinically approved. This review includes an overview of Huntington\u2019s disease, from its genetic aetiology to clinical presentation and its pathogenic manifestation. An updated view of molecular mechanisms and the latest therapeutic developments will also be discussed.<\/jats:p>","DOI":"10.3390\/ijms241613021","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T08:53:31Z","timestamp":1692608011000},"page":"13021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":161,"title":["From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington\u2019s Disease Research"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7267-013X","authenticated-orcid":false,"given":"Andrew","family":"Jiang","sequence":"first","affiliation":[{"name":"Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7935-2399","authenticated-orcid":false,"given":"Renee R.","family":"Handley","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Lehnert","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8166-4014","authenticated-orcid":false,"given":"Russell G.","family":"Snell","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,21]]},"reference":[{"key":"ref_1","first-page":"317","article-title":"On chorea. 1872","volume":"26","author":"Huntington","year":"1872","journal-title":"Med. 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