{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:36:33Z","timestamp":1787841393424,"version":"build-2784847793"},"reference-count":37,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GMR23T1059"],"award-info":[{"award-number":["GMR23T1059"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GMR23T1216"],"award-info":[{"award-number":["GMR23T1216"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Research Council, Advanced Grant","award":["742436"],"award-info":[{"award-number":["742436"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Huntington's Disease"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>\n                    Somatic instability (SI) of the CAG tract in\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    is a major driver of neurodegeneration of Spiny Projection Neurons (SPNs), the primary neuronal subtype affected in Huntington's disease (HD). SPNs can accumulate hundreds of CAG repeats during a patient's lifetime, and once the expansion exceeds \u223c150 CAGs, they acquire distinct, cell-autonomous transcriptional alterations that ultimately contribute to degeneration. Here, we developed the \u201cHD-Phase-Model\u201d, a mathematical framework designed to identify \u201csuper-expanded\u201d SPNs without repeat sizing, by leveraging the only available single-nucleus HD post-mortem dataset that provides both transcriptional profile and matched\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    CAG sizes. After validating model performance on the test data, we applied it to independent single-nucleus datasets lacking CAG sizing information and across multiple brain regions. In all cases, the model consistently detected SPNs populations with convergent transcriptional dysregulation signatures indicative of extreme CAG expansion.\n                  <\/jats:p>\n                  <jats:p>Importantly, although the model was trained on caudate SPNs, we observed highly similar dysregulation patterns in putamen and accumbens, while no evidence of super-expansion was found in SPNs from Alzheimer's and Parkinson's disease donors.<\/jats:p>\n                  <jats:p>\n                    Together, these findings demonstrate that transcriptional profiles alone can serve as predictors of\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    CAG size, enabling systematic identification of super-expanded SPNs and providing insights into HD-specific neurodegenerative mechanisms.\n                  <\/jats:p>","DOI":"10.1177\/18796397261443137","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T14:13:36Z","timestamp":1776694416000},"page":"408-420","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Towards AI-driven prediction of\n                    <i>HTT<\/i>\n                    CAG size in super-expanded human spiny projection neurons from Huntington disease donors"],"prefix":"10.1177","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1192-0684","authenticated-orcid":false,"given":"Simone","family":"Maestri","sequence":"first","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano"},{"name":"Istituto Nazionale di Genetica Molecolare"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6020-1287","authenticated-orcid":false,"given":"Davide","family":"Scalzo","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano"},{"name":"Istituto Nazionale di Genetica Molecolare"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4812-3809","authenticated-orcid":false,"given":"Martina","family":"Zobel","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano"},{"name":"Istituto Nazionale di Genetica Molecolare"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9793-9644","authenticated-orcid":false,"given":"Dario","family":"Besusso","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano"},{"name":"Istituto Nazionale di Genetica Molecolare"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano"},{"name":"Istituto Nazionale di Genetica Molecolare"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"e_1_3_2_2_2","unstructured":"Caron NS Wright GE and Hayden MR. Huntington disease. In: Adam MP Mirzaa GM Pagon RA et al. (eds) GeneReviews(\u00ae). Seattle WA: University of Washington 1993. Available at: https:\/\/pubmed.ncbi.nlm.nih.gov\/20301482\/."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.17.2539"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg352"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/70598"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg056"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.04.007"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.036"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.003"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1204"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa139"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01653-6"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.12.009"},{"key":"e_1_3_2_15_2","article-title":"Long somatic DNA-repeat expansion drives neurodegeneration in Huntington\u2019s disease","volume":"0","author":"Handsaker RE","year":"2025","unstructured":"Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington\u2019s disease. Cell 2025; 0.","journal-title":"Cell"},{"key":"e_1_3_2_16_2","article-title":"Navigating triplet repeats sequencing: concepts, methodological challenges and perspective for Huntington\u2019s disease","author":"Maestri S","year":"2024","unstructured":"Maestri S, Scalzo D, Damaggio G, et al. Navigating triplet repeats sequencing: concepts, methodological challenges and perspective for Huntington\u2019s disease. Nucleic Acids Res 2024. 10.1093\/nar\/%20gkae1155%20(in%20press).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.01.031"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adn4600"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.04.015"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-02054-5"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"e_1_3_2_22_2","unstructured":"Wickham H Chang W Henry L et al. ggplot2: Create Elegant Data Visualisations Using the Grammar of Graphics. 2023."},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v033.i01"},{"key":"e_1_3_2_24_2","unstructured":"Pasek J Tahk A Culter G et al. weights: Weighting and Weighted Statistics v1.1.2. 2025. Available at: https:\/\/CRAN.Rproject.org\/package=weights."},{"key":"e_1_3_2_25_2","unstructured":"Becker R. The New S Language Chapman and Hall\/CRC New York. 2018."},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50626-0"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.06.021"},{"key":"e_1_3_2_28_2","first-page":"346","article-title":"Human striatal glia differentially contribute to AD- and PD-specific neurodegeneration","volume":"3","author":"Xu J","year":"2023","unstructured":"Xu J, Farsad HL, Hou Y, et al. Human striatal glia differentially contribute to AD- and PD-specific neurodegeneration. Nat Aging 2023; 3: 346\u2013365.","journal-title":"Nat Aging"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-198511000-00003"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.31232"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.266909"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2024.11.003"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.02.008"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2015.11.005"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4532"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0075-7"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50877-x"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.64898\/2025.12.09.688862"}],"container-title":["Journal of Huntington's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/18796397261443137","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/18796397261443137","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/18796397261443137","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:53:04Z","timestamp":1787838784000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/18796397261443137"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":37,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1177\/18796397261443137"],"URL":"https:\/\/doi.org\/10.1177\/18796397261443137","relation":{},"ISSN":["1879-6397","1879-6400"],"issn-type":[{"value":"1879-6397","type":"print"},{"value":"1879-6400","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]}}}