{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:34:55Z","timestamp":1790674495086,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T00:00:00Z","timestamp":1674172800000},"content-version":"vor","delay-in-days":22,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CHDI Foundation"},{"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":[[2022,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntingtin-lowering approaches that target huntingtin expression are a major focus for therapeutic intervention for Huntington\u2019s disease. When the cytosine, adenine and guanine repeat is expanded, the huntingtin pre-mRNA is alternatively processed to generate the full-length huntingtin and HTT1a transcripts. HTT1a encodes the aggregation-prone and highly pathogenic exon 1 huntingtin protein. In evaluating huntingtin-lowering approaches, understanding how the targeting strategy modulates levels of both transcripts and the huntingtin protein isoforms that they encode will be essential. Given the aggregation-propensity of exon 1 huntingtin, the impact of a given strategy on the levels and subcellular location of aggregated huntingtin will need to be determined. We have developed and applied sensitive molecular approaches to monitor the levels of aggregated and soluble huntingtin isoforms in tissue lysates. We have used these, in combination with immunohistochemistry, to map the appearance and accumulation of aggregated huntingtin throughout the CNS of zQ175 mice, a model of Huntington\u2019s disease frequently chosen for preclinical studies. Aggregation analyses were performed on tissues from zQ175 and wild-type mice at monthly intervals from 1 to 6 months of age. We developed three homogeneous time-resolved fluorescence assays to track the accumulation of aggregated huntingtin and showed that two of these were specific for the exon 1 huntingtin protein. Collectively, the homogeneous time-resolved fluorescence assays detected huntingtin aggregation in the 10 zQ175 CNS regions by 1\u20132 months of age. Immunohistochemistry with the polyclonal S830 anti-huntingtin antibody showed that nuclear huntingtin aggregation, in the form of a diffuse nuclear immunostain, could be visualized in the striatum, hippocampal CA1 region and layer IV of the somatosensory cortex by 2 months. That this diffuse nuclear immunostain represented aggregated huntingtin was confirmed by immunohistochemistry with a polyglutamine-specific antibody, which required formic acid antigen retrieval to expose its epitope. By 6 months of age, nuclear and cytoplasmic inclusions were widely distributed throughout the brain. Homogeneous time-resolved fluorescence analysis showed that the comparative levels of soluble exon 1 huntingtin between CNS regions correlated with those for huntingtin aggregation. We found that soluble exon 1 huntingtin levels decreased over the 6-month period, whilst those of soluble full-length mutant huntingtin remained unchanged, data that were confirmed for the cortex by immunoprecipitation and western blotting. These data support the hypothesis that exon 1 huntingtin initiates the aggregation process in knock-in mouse models and pave the way for a detailed analysis of huntingtin aggregation in response to huntingtin-lowering treatments.<\/jats:p>","DOI":"10.1093\/braincomms\/fcad010","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T10:00:02Z","timestamp":1674208802000},"source":"Crossref","is-referenced-by-count":38,"title":["Early detection of exon 1 huntingtin aggregation in zQ175 brains by molecular and histological approaches"],"prefix":"10.1093","volume":"5","author":[{"given":"Edward J","family":"Smith","sequence":"first","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirupa","family":"Sathasivam","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , 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":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , 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":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Mason","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7477-4226","authenticated-orcid":false,"given":"Casandra","family":"Gomez-Paredes","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget A","family":"Taxy","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , 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":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Ast","sequence":"additional","affiliation":[{"name":"Neuroproteomics, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association , Berlin 13125 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3320-8284","authenticated-orcid":false,"given":"Franziska","family":"Schindler","sequence":"additional","affiliation":[{"name":"Neuroproteomics, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association , Berlin 13125 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangchuang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department Psychiatry and Behavioral Sciences; Department Neuroscience, Johns Hopkins University School of Medicine , Baltimore, MD 21287 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5933-6308","authenticated-orcid":false,"given":"Wenzhen","family":"Duan","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department Psychiatry and Behavioral Sciences; Department Neuroscience, Johns Hopkins University School of Medicine , Baltimore, MD 21287 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erich E","family":"Wanker","sequence":"additional","affiliation":[{"name":"Neuroproteomics, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association , Berlin 13125 , Germany"}],"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 and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London , London WC1N 3BG , 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