A Drosophila model of Pontocerebellar Hypoplasia reveals a critical role for the RNA exosome in neurons

• DOI: 10.1371/journal.pgen.1008901
• Publication Date: 2020-07-09T17:53:40Z
• Authors: Derrick J. Morton; Binta Jalloh; Lily Kim; Isaac Kremsky; Rishi J. Nair; Khuong B. Nguyen; J. Christopher Ro...; Maria C. Sterrett; Brianna Brown; Thalia Le; Maya C. Karkare; Kathryn D. McGaughey; Shaoyi Sheng; Sara W. Leung; Milo B. Fasken; Kenneth H. Moberg; Anita H. Corbett
• Keywords: Exosome complex; Exosome

The RNA exosome is an evolutionarily-conserved ribonuclease complex critically important for precise processing and/or complete degradation of a variety cellular RNAs. recent discovery that mutations in genes encoding structural subunits cause tissue-specific diseases makes defining the role this within specific tissues important. Mutations component 3 (EXOSC3) gene Pontocerebellar Hypoplasia Type 1b (PCH1b), autosomal recessive neurologic disorder. majority disease-linked are missense alter regions EXOSC3. defects caused by these amino acid changes EXOSC3 challenging to understand based on current models function with only limited analysis any multicellular model vivo. goal study provide insight into how impact exosome. To assess roles and requirements Drosophila ortholog termed Rrp40, we utilized RNAi drivers. Depletion Rrp40 different reveals general requirement development many including brain, but also highlight age-dependent neurons. functional consequences substitutions PCH1b, used CRISPR/Cas9 editing technology generate flies exosome-linked disease. These show reduced viability; however, surviving animals exhibit spectrum behavioral morphological phenotypes. RNA-seq mutants increases steady-state levels mRNAs ncRNAs, some which central neuronal function. In particular, Arc1 mRNA, encodes key regulator synaptic plasticity, increased mutants. Taken together, defines tissues/cell types provides occur PCH1b can contribute dysfunction.