iScience | VOL. 25
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Asymmetric inheritance of RNA toxicity in C.elegans expressing CTG repeats.

Publication Date May 20, 2022

Abstract

Nucleotide 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 use Caenorhabditis elegans bearing 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.

Concepts
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RNA Toxicity
Intergenerational Epigenetic Inheritance
Manifestation In Infants
Small RNA Pathways
Intergenerational Inheritance
Asymmetric Inheritance
RNAi Machinery
Transcriptomic Changes
Disease Phenotypes
Small RNA

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