Armakola M~Gitler AD, 2012

Pubmed ID 23104007
Title Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.
Authors 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
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.
Citation Nat. Genet. 2012; 44:1302-9
Data abstract Deletion collection was screened for enhancers and suppressors of TDP-43 toxicity.

Datasets

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Paper Phenotype Condition Medium Collection Tested mutants Data Details
Armakola M~Gitler AD, 2012 growth (colony size) TDP-43 toxicity SC - Ura, Gal [2%] hap a (post-SGA) N/A Quantitative
Armakola M~Gitler AD, 2012 growth (colony size) TDP-43 toxicity SC - Ura, Gal [2%] het N/A Quantitative

Curation history

Tested strains

Aug. 28, 2020 Undefined.

Data

Aug. 28, 2020 Undefined.