{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:13:53Z","timestamp":1790741633243,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,7,7]],"date-time":"2019-07-07T00:00:00Z","timestamp":1562457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS077962"],"award-info":[{"award-number":["NS077962"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001671","name":"Hereditary Disease Foundation","doi-asserted-by":"publisher","award":["John J Wasmuth Fellowship"],"award-info":[{"award-number":["John J Wasmuth Fellowship"]}],"id":[{"id":"10.13039\/100001671","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Huntington\u2019s disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin (\n                    <jats:italic>HTT<\/jats:italic>\n                    ) gene. The Q140 and\n                    <jats:italic>Hdh<\/jats:italic>\n                    Q150 knock\u2010in HD mouse models were generated such that\n                    <jats:italic>Hdh<\/jats:italic>\n                    Q150 mice have an expanded CAG repeat inserted into the mouse\n                    <jats:italic>Htt<\/jats:italic>\n                    gene, whereas in the Q140s, mouse exon 1\n                    <jats:italic>Htt<\/jats:italic>\n                    was replaced with a mutated version of human exon 1. By standardizing mouse strain background, breeding to homozygosity and employing sensitive behavioral tests, we demonstrate that the onset of behavioral phenotypes occurs earlier in the Q140 than the\n                    <jats:italic>Hdh<\/jats:italic>\n                    Q150 knock\u2010in mouse models and that huntingtin (HTT) aggregation appears earlier in the striata of Q140 mice. We have previously found that the incomplete splicing of mutant\n                    <jats:italic>HTT<\/jats:italic>\n                    from exon 1 to exon 2 results in the production of a small polyadenylated transcript that encodes the highly pathogenic mutant HTT exon 1 protein. In this report, we have identified a functional consequence of the sequence differences between these two models at the RNA level, in that the level of incomplete splicing, and of the mutant exon 1 HTT protein, are greater in the brains of Q140 mice. While differences in the human and mouse exon 1 HTT proteins (e.g., proline rich sequences) could also contribute to the phenotypic differences, our data indicate that the incomplete splicing of\n                    <jats:italic>HTT<\/jats:italic>\n                    and approaches to lower the levels of the exon 1\n                    <jats:italic>HTT<\/jats:italic>\n                    transcript should be pursued as therapeutic targets.\n                  <\/jats:p>","DOI":"10.1002\/jnr.24493","type":"journal-article","created":{"date-parts":[[2019,7,8]],"date-time":"2019-07-08T00:14:24Z","timestamp":1562544864000},"page":"1590-1605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Phenotype onset in Huntington\u2019s disease knock\u2010in mice is correlated with the incomplete splicing of the mutant huntingtin gene"],"prefix":"10.1002","volume":"97","author":[{"given":"Nicholas R.","family":"Franich","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam A.","family":"Hickey","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"},{"name":"Department of Pharmacology University of Tartu Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunni","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina F.","family":"Osborne","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London London UK"},{"name":"UK Dementia Research Institute at UCL University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadira","family":"Ali","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London London UK"},{"name":"UK Dementia Research Institute at UCL University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas H.","family":"Bove","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Lemesre","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata P.","family":"Lerner","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott O.","family":"Zeitlin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Virginia School of Medicine Charlottesville Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Howland","sequence":"additional","affiliation":[{"name":"CHDI Management\/CHDI Foundation Inc. New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Neueder","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London London UK"},{"name":"UK Dementia Research Institute at UCL University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Landles","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London London UK"},{"name":"UK Dementia Research Institute at UCL University College London London UK"}],"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":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London London UK"},{"name":"UK Dementia Research Institute at UCL University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Francoise","family":"Chesselet","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine University of California, Los Angeles Los Angeles California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu504"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.5"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-3-17"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2010.05.004"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<110::AID-GENE2>3.0.CO;2-8"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5334.1990"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2006.12.004"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-170274"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-07-02522.1999"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050717"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1830-07.2007"},{"key":"e_1_2_11_13_1","volume-title":"Mouse models of mental illness and neurological disease: Huntington\u2019s disease","author":"Hickey M. 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