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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Retrotransposon activation is increasingly linked to neurodegenerative diseases.
• SINE-VNTR-Alu (SVA) elements are hominid-specific retrotransposons contributing to genetic diversity.
• X-linked dystonia parkinsonism (XDP) is a striatal neurodegenerative disorder associated with SVA repeat expansion.

Purpose of the Study:

• To investigate the role of the SVA (CCCTCT)n short tandem repeat (STR) in XDP pathogenesis.
• To elucidate the molecular mechanisms by which SVA insertions contribute to neurodegeneration.
• To explore potential therapeutic interventions targeting the pathogenic SVA element.

Main Methods:

• Phenotypic and transcriptomic analysis of XDP and isogenic SVA-deleted striatal organoids.
• Identification and characterization of SVA-derived RNA.
• Assessment of R-loop formation in organoids and brain tissue.
• In vitro knockdown of the hexamer-containing RNA using antisense oligonucleotides.

Main Results:

• SVA insertion in XDP organoids recapitulates neurodegenerative hallmarks, including transcriptional dysregulation, reduced neuronal activity, and apoptosis.
• SVA deletion significantly ameliorates these neurodegenerative phenotypes.
• An (AGAGGG)n hexamer-containing RNA within the SVA increases with maturation and induces R-loop formation.
• Antisense oligonucleotide-mediated knockdown of this RNA rescues apoptosis in XDP organoids.

Conclusions:

• Retrotransposon-derived tandem repeat RNAs can drive neurodegeneration.
• The SVA insertion and its derived RNA are key pathogenic factors in XDP.
• Targeting retrotransposon-derived RNAs offers a potential therapeutic avenue for neurodegenerative diseases like XDP.