The RNA exosome maintains cellular RNA homeostasis by controlling transcript abundance in the brain.

Intracellular ribonucleases (RNases) are essential for maintaining accurate RNA levels. Inherited mutations in genes encoding ubiquitous RNases are associated with human diseases, primarily affecting the nervous system. Recessive mutations in genes encoding the evolutionarily conserved RNA exosome, an RNase complex, cause syndromic neurodevelopmental disorders, such as pontocerebellar hypoplasia type 1b (PCH1b), characterized by progressive neurodegeneration. Here, we establish a CRISPR-Cas9-engineered Drosophila model of PCH1b to investigate the cell-type-specific post-transcriptional regulatory functions of the RNA exosome complex in vivo. Pathogenic variants in Rrp40, a subunit of the complex, disrupt RNA exosome activity, leading to widespread transcriptomic dysregulation in brain-enriched cell populations, including defective rRNA processing. These molecular defects coincide with progressive neurodegeneration and behavioral impairments that track with allele severity. Our findings provide a cell-type-resolved view of RNA exosome function in a fully developed animal brain and underscore the critical role of RNA surveillance in safeguarding transcriptome homeostasis and neuronal integrity.