{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T15:36:01Z","timestamp":1771947361568,"version":"3.50.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Huntington\u2019s disease (HD) remains an incurable and fatal neurodegenerative disease long after CAG-expansion mutation in the huntingtin gene (<jats:italic>HTT<\/jats:italic>) was identified as the cause. The underlying pathological mechanism, whether <jats:italic>HTT<\/jats:italic> loss of function or gain of toxicity results from mutation, remains a matter of debate.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> In this study, we genetically modulated wild-type or mutant <jats:italic>HTT<\/jats:italic> expression levels in isogenic human embryonic stem cells to systematically investigate their contribution to HD-specific phenotypes.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Using highly reproducible and quantifiable <jats:italic>in vitro<\/jats:italic> micropattern-based assays, we observed comparable phenotypes with HD mutation and <jats:italic>HTT<\/jats:italic> depletion. However, halving endogenous wild-type <jats:italic>HTT<\/jats:italic> levels did not strongly recapitulate the HD phenotypes, arguing against a classical loss of function mechanism. Remarkably, expression of CAG-expanded <jats:italic>HTT<\/jats:italic> in non-HD cells induced HD like phenotypes akin to <jats:italic>HTT<\/jats:italic> depletion.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> By corollary, these results indicate a dominant negative effect of mutated <jats:italic>HTT<\/jats:italic> on its wild-type counterpart. Complementation with additional copies of wild-type <jats:italic>HTT<\/jats:italic> ameliorated the HD-associated phenotypes, strongly supporting a classical dominant negative mechanism. Understanding the molecular basis of this dominant negative effect will guide the development of efficient clinical strategies to counteract the deleterious impact of mutant <jats:italic>HTT<\/jats:italic> on the wild-type <jats:italic>HTT<\/jats:italic> function.<\/jats:p>","DOI":"10.3389\/fcell.2023.1252521","type":"journal-article","created":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T10:47:08Z","timestamp":1693565228000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Huntingtin CAG-expansion mutation results in a dominant negative effect"],"prefix":"10.3389","volume":"11","author":[{"given":"Tiago L.","family":"Laundos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Cheang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"De Santis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco M.","family":"Piccolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali H.","family":"Brivanlou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/BF02257483","article-title":"Structure and expression of the Huntington\u2019s disease gene: evidence against simple inactivation due to an expanded CAG repeat","volume":"20","author":"Ambrose","year":"1994","journal-title":"Somat. 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