title: In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models.
abstract: Myotonic dystrophy type 1 (DM1) is caused by the expansion of noncoding CTG repeats in the dystrophia myotonica-protein kinase gene. Mutant transcripts form CUG hairpins that sequester RNA-binding factors into nuclear foci, including Muscleblind-like-1 protein (MBNL1), which regulate alternative splicing and gene expression. To identify molecules that target toxic CUG transcripts in vivo, we performed a positional scanning combinatorial peptide library screen using a Drosophila model of DM1. The screen identified a D-amino acid hexapeptide (ABP1) that reduced CUG foci formation and suppressed CUG-induced lethality and muscle degeneration when administered orally. Transgenic expression of natural, L-amino acid ABP1 analogues reduced CUG-induced toxicity in fly eyes and muscles. Furthermore, ABP1 reversed muscle histopathology and splicing misregulation of MBNL1 targets in DM1 model mice. In vitro, ABP1 bound to CUG hairpins and induced a switch to a single-stranded conformation. Our findings demonstrate that ABP1 shows antimyotonic dystrophy activity by targeting the core of CUG toxicity.
authors: Department of Genetics, University of Valencia, Burjassot E-46100, Spain.
authors: Amparo
authors: A
authors: García-López
authors: Beatriz
authors: B
authors: Llamusí
authors: Mar
authors: M
authors: Orzáez
authors: Enrique
authors: E
authors: Pérez-Payá
authors: Ruben D
authors: RD
authors: Artero
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila; D055808:Drug Discovery; D051379:Mice; D009132:Muscles / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism*; D019151:Peptide Library; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C585516:DMPK protein, mouse; D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D009842:Oligopeptides; D019151:Peptide Library; D016601:RNA-Binding Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases