{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Armakola M"],"funding":["NCRR NIH HHS","NIA NIH HHS","NIAID NIH HHS","NINDS NIH HHS","NIH HHS","NIGMS NIH HHS"],"pagination":["1302-9"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC3510335"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["44(12)"],"pubmed_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."],"journal":["Nature genetics"],"pubmed_title":["Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models."],"pmcid":["PMC3510335"],"funding_grant_id":["RR18928","2P01AG02074","GM084279","K08 NS072233","1DP2OD004417","1DP2OD002177","R01 GM084279","R01 NS065317","R01 NS039074","R21 NS067354","NS045491","DP2 OD004417","NS072233","P30 AI027763","R01 GM098101","GM098101","R01 GM084448","NS39074","NS065317","DP2 OD002177","NS067354","P50 GM081879","GM084448","C06 RR018928","GM081879"],"pubmed_authors":["Scarborough EA","Fang X","Krogan NJ","Higgins MJ","Finkbeiner S","Gitler AD","Diaz Z","Armakola M","Shorter J","Barmada SJ","Figley MD","Farese RV"],"additional_accession":[]},"is_claimable":false,"name":"Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.","description":"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.","dates":{"release":"2012-01-01T00:00:00Z","publication":"2012 Dec","modification":"2020-10-31T08:03:56Z","creation":"2019-03-27T01:01:12Z"},"accession":"S-EPMC3510335","cross_references":{"pubmed":["23104007"],"doi":["10.1038/ng.2434"]}}