Hsu, Tsung-YuanTsung-YuanHsuYang, Hsin-YaHsin-YaYangHsieh, Lin-ShiangLin-ShiangHsiehChen, Kuan-YenKuan-YenChenChiou, Guang-YuhGuang-YuhChiouChen, Albert Y.Albert Y.ChenL'Etoile, Noelle D.Noelle D.L'EtoileTZONG-LIN JAY SHIEHHagerman, Paul J.Paul J.HagermanJuang, Bi-TzenBi-TzenJuang2026-03-162026-03-162026-02-20https://www.scopus.com/record/display.uri?eid=2-s2.0-105029533846&origin=resultslisthttps://scholars.lib.ntu.edu.tw/handle/123456789/736368Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by CGG repeat expansions in FMR1, leading to RNA toxicity and toxic FMRpolyG peptide from abnormal translation. Using a Caenorhabditis elegans model, we generated single-copy insertions of the human FMR1 5′ UTR containing 0, 16, or 99 CGG repeats under a pan-neuronal promoter. Worms expressing 99 CGG repeats showed impaired motility, altered neuronal morphology, and disrupted miRNA homeostasis. Co-expression of PASH-1, the C. elegans ortholog of a miRNA-processing DGCR8 sequestered in FXTAS, mitigated both RNA- and peptide-mediated toxicity, restoring locomotion, neuronal structure, and miRNA regulation balance. Removing FMRpolyG improved movement by ∼50%, suggesting RNA toxicity is the primary pathogenesis. Glial 99 CGG expression altered nearby neuronal cilia, disrupting olfaction without affecting movement, revealing non-cell-autonomous toxicity. These findings establish the protective role of PASH-1 against CGG-induced neurotoxicity and underscore C. elegans as a model for dissecting FXTAS mechanisms and exploring therapeutic strategies.truecell biologyNeurosciencejournal article10.1016/j.isci.2026.1148122-s2.0-105029533846