Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease 
primarily affecting motor neurons. Mutations in the gene encoding TDP-43 cause 
some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in 
degenerating neurons of most individuals with ALS. Thus, strategies aimed at 
targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here, 
we report results from two genome-wide loss-of-function TDP-43 toxicity 
suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was 
deletion of DBR1, which encodes an RNA lariat debranching enzyme. We show that, 
in the absence of Dbr1 enzymatic activity, intronic lariats accumulate in the 
cytoplasm and likely act as decoys to sequester TDP-43, preventing it from 
interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of 
Dbr1 in a human neuronal cell line or in primary rat neurons is also sufficient 
to rescue TDP-43 toxicity. Our findings provide insight into TDP-43-mediated 
cytotoxicity and suggest that decreasing Dbr1 activity could be a potential 
therapeutic approach for ALS.