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)<sub>n</sub> 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)<sub>n</sub> 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.
Authors
- Alejandra E. McCord
- Taylor A. Evans (ORCID: https://orcid.org/0000-0002-0098-2871)
- Michelle Sy (ORCID: https://orcid.org/0000-0001-7130-7569)
- Apuã C.M. Paquola (ORCID: https://orcid.org/0000-0002-1329-6870)
- Hunter H. Giles (ORCID: https://orcid.org/0000-0002-2340-5444)
- Tomoyo Sawada (ORCID: https://orcid.org/0000-0002-2280-6238)
- G. Paul Legarda
- Jennifer A. Erwin (ORCID: https://orcid.org/0000-0002-6784-9290)
- Alan P. R. Lorenzetti (ORCID: https://orcid.org/0000-0002-0291-248X)
- Edwin L. Muñoz
- Bruno Henrique Silva Araújo (ORCID: https://orcid.org/0000-0003-0012-4217)
- Cid Czarina E. Diesta (ORCID: https://orcid.org/0000-0003-3068-1065)
- Cédric Bardy (ORCID: https://orcid.org/0000-0001-8321-0852)
- Laura D’Ignazio (ORCID: https://orcid.org/0000-0002-1707-4773)
- Michael Zabolocki (ORCID: https://orcid.org/0000-0002-1856-5523)
- Bareera Qamar
- Micaela G. Murcar (ORCID: https://orcid.org/0000-0003-3050-7964)
- D. Cristopher Bragg (ORCID: https://orcid.org/0000-0003-3203-6262)
- Mark C. Ang (ORCID: https://orcid.org/0000-0003-1292-9493)
- André R. Barbosa (ORCID: https://orcid.org/0000-0003-4547-531X)
- M. Salvie Velasco-Andrada
- Cara Fernandez‐Cerado
- Arthur Sant’Anna Feltrin (ORCID: https://orcid.org/0000-0002-1810-2203)
- Bonna Sheehan
- Yanhong Wang (ORCID: https://orcid.org/0009-0009-1647-5581)
- Ellen B. Penney
Institutions
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Makati Medical Center (PH)
- Massachusetts General Hospital (US)
- South Australian Health and Medical Research Institute (AU)
- Lieber Institute for Brain Development (US)
- University of the Philippines Manila (PH)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1016/j.celrep.2025.115812
- Citations
- 1
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.91
Funders
- Massachusetts General Hospital
- Maryland Stem Cell Research Fund