Abstract
We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA–binding proteins as candidates to modify DM1 pathogenesis using a well established Drosophila model of the disease. The screen revealed smaug as a powerful modulator of CUG-induced toxicity. Increasing smaug levels prevents muscle wasting and restores muscle function, while reducing its function exacerbates CUG-induced phenotypes. Using human myoblasts, we show physical interactions between human Smaug (SMAUG1/SMAD4A) and CUGBP1. Increased levels of SMAUG1 correct the abnormally high nuclear accumulation of CUGBP1 in myoblasts from DM1 patients. In addition, augmenting SMAUG1 levels leads to a reduction of inactive CUGBP1-eIF2α translational complexes and to a correction of translation of MRG15, a downstream target of CUGBP1. Therefore, Smaug suppresses CUG-mediated muscle wasting at least in part via restoration of translational activity of CUGBP1.
Highlights
Myotonic Dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder that has become a paradigm of a class of diseases caused by RNA toxicity
Since DM1 is caused by expansion of an untranslated transcript, and MBNL1 and CUGBP1 are themselves RNAbinding proteins, we hypothesized that DM1 modifier genes may be enriched among genes encoding RNA binding proteins (RNABPs)
We screened a collection of 93 loss of function and 17 overexpression alleles in 73 RNA-BP genes for their ability to modulate pathogenesis caused by expanded CUG repeats
Summary
Myotonic Dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder that has become a paradigm of a class of diseases caused by RNA toxicity. The mutant mRNA leads to increased steady-state levels of CUGBP1 (a.k.a CELF1) [8,9] through its stabilization as a result of PKC phosphorylation [10]. Both MBNL1 and CUGBP1 are RNA-binding proteins involved in regulation of splicing [11,12,13,14], and aberrant splicing of the insulin receptor [12], muscle-specific chloride channel [13,15] and many other genes [16,17] occur in DM1. MBNL1 overexpression ameliorates, muscle wasting in a Drosophila DM1 model [18], and myotonia and splicing aberrations in mouse models [19]
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