{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T21:51:26Z","timestamp":1782856286268,"version":"3.54.5"},"posted":{"date-parts":[[2024,7,13]]},"group-title":"Neuroscience","reference-count":105,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,15]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Modifiers of Huntington\u2019s disease (HD) include mismatch repair (MMR) genes; however, their underlying disease-altering mechanisms remain unresolved. Knockout (KO) alleles for 9 HD GWAS modifiers\/MMR genes were crossed to the Q140 Huntingtin (mHtt) knock-in mice to probe such mechanisms. Four KO mice strongly (\n                  <jats:italic>Msh3<\/jats:italic>\n                  and\n                  <jats:italic>Pms1<\/jats:italic>\n                  ) or moderately (\n                  <jats:italic>Msh2<\/jats:italic>\n                  and\n                  <jats:italic>Mlh1<\/jats:italic>\n                  ) rescue a triad of adult-onset, striatal medium-spiny-neuron (MSN)-selective phenotypes: somatic\n                  <jats:italic>Htt<\/jats:italic>\n                  DNA CAG-repeat expansion, transcriptionopathy, and mHtt protein aggregation. Comparatively, Q140 cortex also exhibits an analogous, but later-onset, pathogenic triad that is\n                  <jats:italic>Msh3<\/jats:italic>\n                  -dependent. Remarkably, Q140\/homozygous Msh3-KO lacks visible mHtt aggregates in the brain, even at advanced ages (20-months). Moreover,\n                  <jats:italic>Msh3<\/jats:italic>\n                  -deficiency prevents striatal synaptic marker loss, astrogliosis, and locomotor impairment in HD mice. Purified Q140 MSN nuclei exhibit highly linear age-dependent mHtt DNA repeat expansion (i.e. repeat migration), with modal-CAG increasing at +8.8 repeats\/month (R\n                  <jats:sup>2<\/jats:sup>\n                  =0.98). This linear rate is reduced to 2.3 and 0.3 repeats\/month in Q140 with Msh3 heterozygous and homozygous alleles, respectively. Our study defines somatic\n                  <jats:italic>Htt<\/jats:italic>\n                  CAG-repeat thresholds below which there are no detectable mHtt nuclear or neuropil aggregates. Mild transcriptionopathy can still occur in Q140 mice with stabilized\n                  <jats:italic>Htt<\/jats:italic>\n                  140-CAG repeats, but the majority of transcriptomic changes are due to somatic repeat expansion. Our analysis reveals 479 genes with expression levels highly correlated with modal-CAG length in MSNs. Thus, our study mechanistically connects HD GWAS genes to selective neuronal vulnerability in HD, in which\n                  <jats:italic>Msh3<\/jats:italic>\n                  and\n                  <jats:italic>Pms1<\/jats:italic>\n                  set the linear rate of neuronal mHtt CAG-repeat migration to drive repeat-length dependent pathogenesis; and provides a preclinical platform for targeting these genes for HD suppression across brain regions.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>Msh3 and Pms1 are genetic drivers of sequential striatal and cortical pathogenesis in Q140 mice by mediating selective CAG-repeat migration in HD vulnerable neurons.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.07.09.602815","type":"posted-content","created":{"date-parts":[[2024,7,14]],"date-time":"2024-07-14T02:40:14Z","timestamp":1720924814000},"source":"Crossref","is-referenced-by-count":12,"title":["Msh3 and Pms1 Set Neuronal CAG-repeat Migration Rate to Drive Selective Striatal and Cortical Pathogenesis in HD Mice"],"prefix":"10.64898","author":[{"given":"Nan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Langfelder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalini","family":"Ramanathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Plascencia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuying","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Vaca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linna","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo E.","family":"Dionisio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brinda C.","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Vogt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4110-3589","authenticated-orcid":false,"given":"Steve","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"Aaronson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Rosinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3705-7935","authenticated-orcid":false,"given":"X. 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