GeneticSNUPNvariants cause spinocerebellar atrophy by disrupting global splicing in Purkinje cells

Abstract

AbstractWe identified genetic variants in theSNUPNgene, which encodes the adapter protein snurportin-1 for the nuclear import of U1 snRNPs, in two families affected by spinocerebellar ataxia. We have elucidated the pathogenicity of these variants and the molecular pathomechanisms underlying this disease by assessing mutant snurportin-1 propertiesin vitro, cerebella at the morphological and molecular levelsex vivo, and motor functions inSnupn-variant knocked-in micein vivo. Mutant snurportin-1 impaired nuclear-cytosol shuttling, leading to defective nuclear transport of U1 snRNPs in cerebellar Purkinje cells. This resulted in aberrant splicing and expression of genes essential for Purkinje cell development and impaired dendrite formation. The malformation of Purkinje cell dendrites resulted in hypoplasia and premature migration of granule cell precursors and interneurons, leading to abnormal lobe development and atrophy in the cerebellum.