A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1

Abstract

Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) and type 2 (DM2), respectively. A gain-of-function of these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 and resultant loss of activity of these proteins. To study pathogenic mechanisms of CCUG-repeat expansions in an animal model, we created a fly model of DM2 that expresses pure, uninterrupted CCUG-repeat expansions ranging from 16 to 720 repeats in length. We show that this fly model for DM2 recapitulates key features of human DM2 including RNA repeat-induced toxicity, ribonuclear foci formation and changes in alternative splicing. Interestingly, expression of two isoforms of MBNL1, MBNL1₃₅ and MBNL1₄₀, leads to cleavage and concurrent upregulation of the levels of the RNA-repeat transcripts, with MBNL1₄₀ having more significant effects than MBNL1₃₅. This property is shared with a fly CUG-repeat expansion model. Our results suggest a novel mechanism for interaction between the pathogenic RNA repeat expansions of myotonic dystrophy and MBNL1.