A hexamer tandem repeat RNA embedded within an SVA retrotransposon drives R-loop formation and neurodegeneration

Retrotransposon activation is emerging as a significant factor in neurodegenerative disease pathogenesis. SINE-VNTR-Alu (SVAs) are hominid-specific retrotransposons that create genetic variation through insertion polymorphisms and variable short tandem repeat (STR) lengths. We investigate how the SVA (CCCTCT)_n STR contributes to the striatal neurodegenerative disorder X-linked dystonia parkinsonism (XDP), where the repeat expansion length within the pathogenic SVA is inversely correlated with age at disease onset. Phenotypic and transcriptomic analysis of XDP and isogenic SVA-deleted striatal organoids reveal that the SVA insertion drives hallmarks of neurodegeneration, including transcriptional dysregulation, decreased neuronal activity, and apoptosis, which are ameliorated by SVA deletion. We identify an (AGAGGG)_n hexamer-containing RNA in the XDP-causing SVA that increases expression during organoid maturation and drives R-loop formation in organoids and brain tissue. Knockdown of the hexamer-containing RNA by antisense oligonucleotides rescues apoptosis in XDP organoids. We demonstrate that a retrotransposon-derived tandem repeat RNA may cause neurodegeneration.