Abstract
Evidence for an RNA gain-of-function toxicity has now been provided for an increasing number of human pathologies. Myotonic dystrophies (DM) belong to a class of RNA-dominant diseases that result from RNA repeat expansion toxicity. Specifically, DM of type 1 (DM1), is caused by an expansion of CUG repeats in the 3′UTR of the DMPK protein kinase mRNA, while DM of type 2 (DM2) is linked to an expansion of CCUG repeats in an intron of the ZNF9 transcript (ZNF9 encodes a zinc finger protein). In both pathologies the mutant RNA forms nuclear foci. The mechanisms that underlie the RNA pathogenicity seem to be rather complex and not yet completely understood. Here, we describe Drosophila models that might help unravelling the molecular mechanisms of DM1-associated CUG expansion toxicity. We generated transgenic flies that express inducible repeats of different type (CUG or CAG) and length (16, 240, 480 repeats) and then analyzed transgene localization, RNA expression and toxicity as assessed by induced lethality and eye neurodegeneration. The only line that expressed a toxic RNA has a (CTG)240 insertion. Moreover our analysis shows that its level of expression cannot account for its toxicity. In this line, (CTG)240.4, the expansion inserted in the first intron of CG9650, a zinc finger protein encoding gene. Interestingly, CG9650 and (CUG)240.4 expansion RNAs were found in the same nuclear foci. In conclusion, we suggest that the insertion context is the primary determinant for expansion toxicity in Drosophila models. This finding should contribute to the still open debate on the role of the expansions per se in Drosophila and in human pathogenesis of RNA-dominant diseases.
Highlights
Myotonic dystrophy type 1 (DM1), called Steinert myotonic dystrophy is a multi-systemic pathology originally described as a neuromuscular disorder [1]
We demonstrate that in the (CTG)240.4 line, the expansion is inserted in an endogenous gene, CG9650, that encodes a zinc finger (ZNF) protein [20,21]
In the present work we wanted to generate Drosophila models to try to understand the molecular basis of CUG expansions toxicity
Summary
Myotonic dystrophy type 1 (DM1), called Steinert myotonic dystrophy is a multi-systemic pathology originally described as a neuromuscular disorder [1] It is an autosomal dominant disease genetically linked to a CTG trinucleotide expansion localized in the 39UTR of DMPK [2,3,4]. Recent work clearly establishes that MBNL1 presence in RNA foci is not sufficient to account for the pathological effect of the expansion as MBLN1 was found to be associated with non pathological nuclear foci [15] The identification of another CUG expanded RNA binding factor, namely hnRNP H is more promising as in hnRNP H depeleted cells, CUG expansions do not form nuclear aggregates [16]
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