Reference Report

Reference
Citation	Le Mée, G., Ezzeddine, N., Capri, M., Aït-Ahmed, O. (2008). Repeat length and RNA expression level are not primary determinants in CUG expansion toxicity in Drosophila models. PLoS ONE 3(1): e1466. (Export to RIS)
FlyBase ID	FBrf0210235
Publication Type	Research paper
PubMed ID	18213375
PubMed 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.
DOI	10.1371/journal.pone.0001466
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Language of Publication	English
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Publication Type	Journal
Abbreviation	PLoS ONE
Title	PLoS ONE
Publication Year	2006-
ISBN/ISSN	1932-6203
Data from Reference
Alleles (16)
	CG9650^CTG-240.4 Ecol\lacZ^{CTG.16.T:Zzzz\CAG} exba^CTG-240.1 Or2a^CTG-480.3 Scer\GAL4^Act5C.PI Scer\GAL4^BG380 Scer\GAL4^Bx-MS1096 Scer\GAL4^da.G32 Scer\GAL4^elav-C155 Scer\GAL4^GMR.PF Scer\GAL4^how-24B Scer\GAL4^otu.PR Zzzz\CAG^{a.Scer\UAS.P\T.240} Zzzz\CAG^{a.Scer\UAS.P\T.480} Zzzz\CAG^{Scer\UAS.P\T.240} Zzzz\CAG^{Scer\UAS.P\T.480}
Constructs (9)
	P{Act5C-GAL4} P{GAL4-da.G32} P{GAL4-ninaE.GMR} P{otu-GAL4.R} P{UASp-CAG.240} P{UASp-CAG.480} P{UASp-CTG.16} P{UASp-CTG.240} P{UASp-CTG.480}
Genes (7)
	CG9650 Ecol\lacZ exba Or2a Scer\GAL4 T:Zzzz\CAG Zzzz\CAG
Insertions (14)
	P{GAL4}BG380 P{GawB}Bx^MS1096 P{GawB}elav^C155 P{GawB}how^24B P{UASp-CAG.240}1 P{UASp-CAG.480}1 P{UASp-CAG.480}2 P{UASp-CTG.240}2 P{UASp-CTG.240}3 P{UASp-CTG.240}CG9650^CTG-240.4 P{UASp-CTG.240}exba^CTG-240.1 P{UASp-CTG.480}1 P{UASp-CTG.480}2 P{UASp-CTG.480}Or2a^CTG-480.3
Natural transposons (1)
	P-element