The amyotrophic lateral sclerosis-associated RNA-binding protein (TDP-43) was linked to the pathogenesis of fragile X-associated tremor/ataxia syndrome (FXTAS). In FXTAS, a CGG repeat expansion in the 5′UTR of the FMR1 gene caused a progressive neurodegeneration in human patients. In a drosophila model of FXTAS, He and colleagues identified TDP-43 as the suppressor of the CGG-induced toxicity, although it required two heterogeneous nuclear ribonucleoproteins (Hrb87F and Hrb98DE) for its activity. In fact, deletions in TDP-43 that prevented the interaction with the two ribonucleoproteins nullified the beneficial effect of TDP-43 function of CGG-repeat toxicity. These results suggest a model in which the repeat expansion of CGG at the 5′UTR and the modified interaction with a RBP are implicated in neurodegenerative disease.44
