Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, Clutario KM, Ling SC, Liang TY, Mazur C, Wancewicz E, Kim AS, Watt A, Freier S, Hicks GG, Donohue JP, Shiue L, Bennett CF, Ravits J, Cleveland DW, Yeo GW.
Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs.
Nat Neurosci. 2012 Nov;15(11):1488-97.
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This is a very important study. The fact that loss of function may underlie at least some of the toxicity of TDP-43 and FUS/TLS mutations in ALS is not itself surprising—a number of previous observations had suggested this. But this work provides additional, powerful evidence for that as a significant part of the disease etiology. In addition, by identifying specific, common target RNAs for these two proteins, this elegant work offers an explanation for the fact that our own laboratory, together with that of Steve Finkbeiner at UCSF, has found that suppression of FUS/TLS toxicity by specific genes and chemical substances usually is accompanied by suppression of TDP-43 toxicity by these same agents, in both model organisms and neuronal cell cultures. Among the common targets identified in this paper may be those that are responsible for the overlapping disease mechanism that seems to apply in these forms of ALS. It is hard to believe that these results won't eventually contribute to finding a treatment for this terrible disease.