Nucleotide repeat expansions can elicit neurodegeneration as RNA by sequestering 
specific RNA-binding proteins, preventing them from performing their normal 
functions. Conversely, mutations in RNA-binding proteins can trigger 
neurodegeneration at least partly by altering RNA metabolism. In Fragile 
X-associated tremor/ataxia syndrome (FXTAS), a CGG repeat expansion in the 5'UTR 
of the fragile X gene (FMR1) leads to progressive neurodegeneration in patients 
and CGG repeats in isolation elicit toxicity in Drosophila and other animal 
models. Here, we identify the amyotrophic lateral sclerosis (ALS)-associated 
RNA-binding protein TAR DNA-binding protein (TDP-43) as a suppressor of CGG 
repeat-induced toxicity in a Drosophila model of FXTAS. The rescue appears 
specific to TDP-43, as co-expression of another ALS-associated RNA-binding 
protein, FUS, exacerbates the toxic effects of CGG repeats. Suppression of CGG 
RNA toxicity was abrogated by disease-associated mutations in TDP-43. TDP-43 
does not co-localize with CGG RNA foci and its ability to bind RNA is not 
required for rescue. TDP-43-dependent rescue does, however, require fly hnRNP 
A2/B1 homologues Hrb87F and Hrb98DE. Deletions in the C-terminal domain of 
TDP-43 that preclude interactions with hnRNP A2/B1 abolish TDP-43-dependent 
rescue of CGG repeat toxicity. In contrast, suppression of CGG repeat toxicity 
by hnRNP A2/B1 is not affected by RNAi-mediated knockdown of the fly TDP-43 
orthologue, TBPH. Lastly, TDP-43 suppresses CGG repeat-triggered mis-splicing of 
an hnRNP A2/B1-targeted transcript. These data support a model in which TDP-43 
suppresses CGG-mediated toxicity through interactions with hnRNP A2/B1 and 
suggest a convergence of pathogenic cascades between repeat expansion disorders 
and RNA-binding proteins implicated in neurodegenerative disease.