Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.
Nat Genet
; 44(12): 1302-9, 2012 Dec.
Article
in En
| MEDLINE
| ID: mdl-23104007
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
RNA Nucleotidyltransferases
/
DNA-Binding Proteins
/
Amyotrophic Lateral Sclerosis
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2012
Document type:
Article
Affiliation country:
United States