Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models

Nat Genet. 2012 Dec;44(12):1302-9. doi: 10.1038/ng.2434. Epub 2012 Oct 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Animals
  • Cells, Cultured
  • Cerebral Cortex / enzymology
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Gene Deletion
  • Gene Knockdown Techniques
  • Humans
  • Neurons / enzymology
  • RNA Nucleotidyltransferases / antagonists & inhibitors*
  • RNA Nucleotidyltransferases / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Sequence Deletion


  • DNA-Binding Proteins
  • RNA Nucleotidyltransferases
  • RNA debranching enzyme Dbr1, S cerevisiae
  • lariat debranching enzyme
  • mRNA debranching enzyme