{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T09:44:19Z","timestamp":1770371059150,"version":"3.49.0"},"posted":{"date-parts":[[2025,12,15]]},"group-title":"Neuroscience","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CHDI Foundation","award":["A-14814"],"award-info":[{"award-number":["A-14814"]}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["U01 AG0722439"],"award-info":[{"award-number":["U01 AG0722439"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Neurons adapt gene expression to counter aging, yet the mechanisms by which they harness age- related genes to resist neurodegenerative disease remain elusive. We found that transcriptionalaging inversion (TAGI) in the\n                  <jats:italic>Drd1<\/jats:italic>\n                  -expressing striatal neurons (\n                  <jats:italic>Drd1<\/jats:italic>\n                  SNs) of Huntington\u2019s disease (HD) knock-in (\n                  <jats:italic>Hdh<\/jats:italic>\n                  ) mice exhibits discrete patterns against a TAG-like (TAGL) signature. Strikingly, TAGI dynamics may explain disease progression more accurately than TAGL. Moreover, in\n                  <jats:italic>Drd1<\/jats:italic>\n                  SNs, genes affected by 3\u2019UTR accumulation during aging are predisposed to downregulation in aging and deregulation in\n                  <jats:italic>Hdh<\/jats:italic>\n                  mice. By integrating age-related 3\u2019UTR data and\n                  <jats:italic>Hdh<\/jats:italic>\n                  -mice data, we identified a CAG-repeat-dependent network of upregulated genes with compensatory potential. This network features (i)\n                  <jats:italic>Atad-5,<\/jats:italic>\n                  a P CNA unloader that modifies CAG expansion in human HD plasma samples, and (ii)\n                  <jats:italic>CXXC4<\/jats:italic>\n                  (IDAX), an epigenetic regulator whose early-stage upregulation is lost as behavioral symptoms worsen in\n                  <jats:italic>Hdh<\/jats:italic>\n                  mice. Functionally,\n                  <jats:italic>CXXC4<\/jats:italic>\n                  reduces the senescence marker p16INK4a and restores glutamate excitability in human HD iPS cell-derived SNs. Collectively, these findings suggest that\n                  <jats:italic>Drd1<\/jats:italic>\n                  SN resilience capacity against HD relies on discrete age-related patterns and responses transiently activated in early disease stages. The reactivation of specific age-related genes such as\n                  <jats:italic>CXXC4<\/jats:italic>\n                  may notably restore cortico-striatal function in HD.\n                <\/jats:p>","DOI":"10.64898\/2025.12.12.693965","type":"posted-content","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T04:10:11Z","timestamp":1765858211000},"source":"Crossref","is-referenced-by-count":0,"title":["Modeling Huntington\u2019s disease against age-related genes reveals\n                  <i>CXXC4<\/i>\n                  as an epigenetic target to restore DRD1 striatal neuron activity"],"prefix":"10.64898","author":[{"given":"Maialen","family":"Arrieta-Lobo","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris Seine (IBPS), Center for Neuroscience at Sorbonne Universit\u00e9 (NeuroSU), 75005, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Farina","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris Seine (IBPS), Center for Neuroscience at Sorbonne Universit\u00e9 (NeuroSU), 75005, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara Monteagudo","family":"Aboy","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris Seine (IBPS), Center for Neuroscience at Sorbonne Universit\u00e9 (NeuroSU), 75005, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Mair","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clo\u00e9","family":"Mendoza","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris Seine (IBPS), Center for Neuroscience at Sorbonne Universit\u00e9 (NeuroSU), 75005, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huy","family":"Tran","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris Seine (IBPS), Center for Neuroscience at Sorbonne Universit\u00e9 (NeuroSU), 75005, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff","family":"Aaronson","sequence":"additional","affiliation":[{"name":"CHDI Foundation, Princeton, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jim","family":"Rosinski","sequence":"additional","affiliation":[{"name":"CHDI Foundation, Princeton, NJ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Ellerby","sequence":"additional","affiliation":[{"name":"USA. Buck Institute for Research on Aging, Novato, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Brouillet","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris Seine (IBPS), Center for Neuroscience at Sorbonne Universit\u00e9 (NeuroSU), 75005, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Michel","family":"Peyrin","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris Seine (IBPS), Center for Neuroscience at Sorbonne Universit\u00e9 (NeuroSU), 75005, Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Botas","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, 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