{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T08:02:56Z","timestamp":1771056176339,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,11]]},"group-title":"Neuroscience","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["RF1NS114128"],"award-info":[{"award-number":["RF1NS114128"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS114128"],"award-info":[{"award-number":["R01NS114128"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS109150"],"award-info":[{"award-number":["R01NS109150"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Farber Family Foundation"},{"name":"Aldrich Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,11]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  A repeat expansion in\n                  <jats:italic>C9orf72<\/jats:italic>\n                  is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G\n                  <jats:sub>4<\/jats:sub>\n                  C\n                  <jats:sub>2<\/jats:sub>\n                  )\n                  <jats:sub>149<\/jats:sub>\n                  repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous\n                  <jats:italic>C9orf72<\/jats:italic>\n                  to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, glial activation, and sparse phosphorylated TDP-43 pathology. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced\n                  <jats:italic>C9orf72<\/jats:italic>\n                  produces a coherent, mild ALS\/FTD model.\n                <\/jats:p>","DOI":"10.64898\/2026.02.09.704060","type":"posted-content","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:15:22Z","timestamp":1770855322000},"source":"Crossref","is-referenced-by-count":0,"title":["Intrathecal (G\n                  <sub>4<\/sub>\n                  C\n                  <sub>2<\/sub>\n                  )\n                  <sub>149<\/sub>\n                  delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS\/FTD pathological hallmarks"],"prefix":"10.64898","author":[{"given":"Katelyn A.","family":"Russell","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia A.","family":"Shahrabi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suleyman C.","family":"Akerman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA"},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew D.","family":"Byrne","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey D.","family":"Rothstein","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA"},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Trotti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigid K.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron R.","family":"Haeusler","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, 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