摘要：SummaryNucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases and cause RNA toxicity and multisystemic symptoms that worsen with age. Through an unclear mechanism, RNA toxicity can trigger severe disease manifestation in infants if the repeats are inherited from their mother. Here we useCaenorhabditis elegansbearing expanded CUG repeats to show that this asymmetric intergenerational inheritance of toxicity contributes to disease pathogenesis. In addition, we show that this mechanism is dependent on small RNA pathways with maternal repeat-derived small RNAs causing transcriptomic changes in the offspring, reduced motility, and shortened lifespan. We rescued the toxicity phenotypes in the offspring by perturbing the RNAi machinery in the affected hermaphrodites. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring, causing disease phenotypes through intergenerational epigenetic inheritance.Graphical abstractDisplay OmittedHighlights•Maternal origin of expanded CUG repeats induces RNA toxicity inCaenorhabditis elegansoffspring•Offspring of affected hermaphrodites show molecular and phenotypic disease phenotypes•The RNAi machinery is directly related to the maternal inheritance of RNA toxicity•Altering the RNAi machinery in affected hermaphrodites rescues toxicity in offspringMolecular biology; Molecular Genetics; Developmental biology
