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

Maria Armakola, Matthew J. Higgins, Matthew D. Figley, Sami J. Barmada, Emily A. Scarborough, Zamia Diaz, Xiaodong Fang, James Shorter, Nevan J. Krogan, Steven Finkbeiner, Robert V. Farese, Aaron D. Gitler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1302-1309
Number of pages8
JournalNature Genetics
Volume44
Issue number12
DOIs
StatePublished - Dec 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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