Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats
Maya Braun,
Shachar Shoshani,
Joana Teixeira,
Anna Mellul Shtern,
Maya Miller,
Zvi Granot,
Sylvia E.J. Fischer,
Susana M.D. A. Garcia,
Yuval Tabach
Affiliations
Maya Braun
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Shachar Shoshani
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Joana Teixeira
Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00790 Finland
Anna Mellul Shtern
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Maya Miller
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Zvi Granot
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Sylvia E.J. Fischer
Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Susana M.D. A. Garcia
Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00790 Finland; Corresponding author
Yuval Tabach
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Corresponding author
Summary: 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.
