{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:19:45Z","timestamp":1792793985268,"version":"4.5.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T00:00:00Z","timestamp":1657065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["200181\/Z\/15\/B"],"award-info":[{"award-number":["200181\/Z\/15\/B"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CHDI Foundation","id":[{"id":"https:\/\/ror.org\/046eh8t80","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Dementia Research Institute Ltd"},{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100017506","name":"Alzheimer\u2019s Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100017506","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntington disease is caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that is translated into a polyglutamine stretch in the huntingtin protein (HTT). We previously showed that HTT mRNA carrying an expanded CAG repeat was incompletely spliced to generate HTT1a, an exon 1 only transcript, which was translated to produce the highly aggregation-prone and pathogenic exon 1 HTT protein. This occurred in all knock-in mouse models of Huntington\u2019s disease and could be detected in patient cell lines and post-mortem brains. To extend these findings to a model system expressing human HTT, we took advantage of YAC128 mice that are transgenic for a yeast artificial chromosome carrying human HTT with an expanded CAG repeat.<\/jats:p>\n                  <jats:p>We discovered that the HTT1a transcript could be detected throughout the brains of YAC128 mice. We implemented RNAscope to visualize HTT transcripts at the single molecule level and found that full-length HTT and HTT1a were retained together in large nuclear RNA clusters, as well as being present as single transcripts in the cytoplasm. Homogeneous time-resolved fluorescence analysis demonstrated that the HTT1a transcript had been translated to produce the exon 1 HTT protein. The levels of exon 1 HTT in YAC128 mice, correlated with HTT aggregation, supportive of the hypothesis that exon 1 HTT initiates the aggregation process.<\/jats:p>\n                  <jats:p>Huntingtin-lowering strategies are a major focus of therapeutic development for Huntington\u2019s disease. These approaches often target full-length HTT alone and would not be expected to reduce pathogenic exon 1 HTT levels. We have established YAC128 mouse embryonic fibroblast lines and shown that, together with our QuantiGene multiplex assay, these provide an effective screening tool for agents that target HTT transcripts. The effects of current targeting strategies on nuclear RNA clusters are unknown, structures that may have a pathogenic role or alternatively could be protective by retaining HTT1a in the nucleus and preventing it from being translated. In light of recently halted antisense oligonucleotide trials, it is vital that agents targeting HTT1a are developed, and that the effects of HTT-lowering strategies on the subcellular levels of all HTT transcripts and their various HTT protein isoforms are understood.<\/jats:p>","DOI":"10.1093\/brain\/awac241","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T12:59:07Z","timestamp":1657112347000},"page":"4409-4424","source":"Crossref","is-referenced-by-count":51,"title":["Alternative processing of human\n                    <i>HTT<\/i>\n                    mRNA with implications for Huntington\u2019s disease therapeutics"],"prefix":"10.1093","volume":"145","author":[{"given":"Sandra","family":"Fienko","sequence":"first","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9715-6447","authenticated-orcid":false,"given":"Christian","family":"Landles","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirupa","family":"Sathasivam","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean J","family":"McAteer","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4373-1052","authenticated-orcid":false,"given":"Rebecca E","family":"Milton","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8308-3179","authenticated-orcid":false,"given":"Georgina F","family":"Osborne","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel T","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8217-5060","authenticated-orcid":false,"given":"Marie K","family":"Bondulich","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C E","family":"Danby","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jemima","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget A","family":"Taxy","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly B","family":"Kordasiewicz","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals , Carlsbad, CA 92008 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-6305","authenticated-orcid":false,"given":"Gillian P","family":"Bates","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Huntington\u2019s Disease Centre and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,6]]},"reference":[{"key":"2022122116044195700_awac241-B1","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","author":"Bates","year":"2015","journal-title":"Nat Rev Dis 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