• Models and mechanisms of repeat expansion disorders: a worm’s eye view

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    • Keywords

       

      neurodegeneration; Huntington’s disease; amyotrophic lateral sclerosis / frontotemporal degeneration; repeat-associated nonAUG dependent translation; repeat expansion mutation; $Caenorhabditis\; \; elegans$.

    • Abstract

       

      The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed ‘repeat-associated nonAUG dependent (RAN) translation’ paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system Caenorhabditis elegans has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.

    • Author Affiliations

       

      PAIGE RUDICH1 TODD LAMITINA1 2 3

      1. Graduate Program in Cell Biology and Molecular Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
      2. Division of Child Neurology, Department of Pediatrics, Children’sHospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
      3. Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    • Dates

       
  • Journal of Genetics | News

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