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

Laura D'Ignazio; Alan P R Lorenzetti; Ellen B Penney; Taylor A Evans; Bareera Qamar; Alejandra E McCord; Arthur S Feltrin; Andre R Barbosa; Bonna J Sheehan; Bruno Araujo; Hunter H Giles; Yanhong Wang; Tomoyo Sawada; Michael Zabolocki; Micaela Murcar; Cara Fernandez-Cerado; G Paul Legarda; Michelle Sy; M Salvie Velasco-Andrada; Edwin Munoz; Mark C Ang; Cid Czarina E Diesta; Cedric Bardy; D Cristopher Bragg; Apua C M Paquola; Jennifer A Erwin

doi:10.1016/j.celrep.2025.115812

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

Cell Rep. 2025 Jun 19;44(7):115812. doi: 10.1016/j.celrep.2025.115812. Online ahead of print.

Authors

Laura D'Ignazio¹, Alan P R Lorenzetti², Ellen B Penney³, Taylor A Evans¹, Bareera Qamar², Alejandra E McCord², Arthur S Feltrin², Andre R Barbosa², Bonna J Sheehan², Bruno Araujo², Hunter H Giles⁴, Yanhong Wang², Tomoyo Sawada², Michael Zabolocki⁵, Micaela Murcar³, Cara Fernandez-Cerado⁶, G Paul Legarda⁶, Michelle Sy⁶, M Salvie Velasco-Andrada⁶, Edwin Munoz⁷, Mark C Ang⁷, Cid Czarina E Diesta⁸, Cedric Bardy⁵, D Cristopher Bragg³, Apua C M Paquola¹, Jennifer A Erwin⁹

Affiliations

¹ Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
³ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
⁴ Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA 5000, Australia; Flinders Health Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia.
⁶ Sunshine Care Foundation, Roxas City, Capiz, Philippines.
⁷ Department of Pathology, College of Medicine, University of the Philippines, Manila, Philippines.
⁸ Department of Neurosciences, Makati Medical Center, Makati, Philippines.
⁹ Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jennifer.erwins@gmail.com.

PMID: 40540399
DOI: 10.1016/j.celrep.2025.115812

Abstract

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.

Keywords: CP: Molecular biology; CP: Neuroscience; G-quadruplex; G4; R-loop; SVA; XDP; neurodegeneration; repeat; retroelement; retrotransposon; somatic instability.