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) 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) 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.