《Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models》.pdf

A rt i c l e s Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models 1,2,12 3,12 1 4,5 6 Maria Armakola , Matthew J Higgins , Matthew D Figley , Sami J Barmada , Emily A Scarborough , 6 1 6 3,7,8 4,5,9 3,10,11,13 Zamia Diaz , Xiaodong Fang , James Shorter , Nevan J Krogan , Steven Finkbeiner , Robert V Farese Jr Aaron D Gitler1,13 Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in the . d gene encoding TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons e v r of most individuals with ALS. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. e s Here, we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest e r s suppressor of TDP-43 toxicity was deletion of DBR1, which encodes an RNA lariat debranching enzyme. We show that, in the t h absence of Dbr1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43, g i r l preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal l A . cell line or in primary rat neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43–mediated c n cytotoxicity and suggest that decreasing Dbr1 activity could be