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Despite its pathological role, effective therapies remain limited by the lack of safe, potent molecules targeting TDP-43 neurotoxicity. Here we show that the conserved \u03b1-helical region spanning residues 320\u2013340 (conserved region or CR) is a therapeutically actionable target for TDP-43 neurotoxicity. Deletion of CR markedly suppressed TDP-43-induced neuronal death. Structure-based virtual screening identified XL20, a brain-penetrant small molecule that engages CR and confers neuroprotection without affecting TDP-43 splicing activity. XL20 alleviated motor neuron loss, extended survival in TDP-43 p.Ala315Thr ALS mice and enhanced neuronal function in p.Gln331Lys induced pluripotent stem cell-derived human ALS motor neurons. Mechanistically, targeting CR suppressed TDP-43 mitochondrial localization and restored mitochondrial function, likely through liquid\u2013liquid phase separation. Our findings highlight CR as a therapeutic target for TDP-43-associated neurodegeneration and support CR-binding small molecules as therapeutic candidates.\n                  <\/jats:p>","DOI":"10.1038\/s43587-026-01166-3","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:18:37Z","timestamp":1783070317000},"page":"1667-1683","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-9406","authenticated-orcid":false,"given":"Ju","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8021-8645","authenticated-orcid":false,"given":"Devanshi","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyue","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Vicuna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4325-1216","authenticated-orcid":false,"given":"Masaru","family":"Miyagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan P.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8657-0159","authenticated-orcid":false,"given":"Xinglong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"1166_CR1","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1038\/ng.132","volume":"40","author":"E Kabashi","year":"2008","unstructured":"Kabashi, E. et al. 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