Transcriptional Alterations in X-Linked Dystonia-Parkinsonism Caused by the SVA Retrotransposon.

Jelena Pozojevic,Raymond L Rosales,Susen Schaake,Karen Grütz,Varun K A Sreenivasan,Henriette Kirchner,Nathalie Kruse,Jakob Matschke,Joseph Neos Cruz,Joanne Trinh,Joshua Laß,Philip Seibler,Malte Spielmann,Christine Klein,Norbert Brüggemann,Shela Marie Algodon,Ana Westenberger,Cid Czarina E Diesta,Frank J Kaiser,Kristin Schulz,Kristian Händler,Markus Glatzel,Roland Dominic G Jamora,Ronnie Tse,Verónica Yumiceba ,Aleksandar Raković

doi:10.3390/ijms23042231

Abstract

X-linked dystonia–parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.

Highlights

X-linked dystonia–parkinsonism (XDP) is an adult-onset neurodegenerative movement disorder endemic to the Philippines, predominantly affecting men due to theX-linked mode of inheritance
This implies that the expression levels and function of TAF1/TAF1 must be tightly regulated, and any dysregulation could have a plethora of different consequences
While the canonical and neuron-specific TAF1 isoforms differ in only 6 bp that determine the tissue distribution, it is still unclear whether the alternative transcript variant containing the deep intronic region performs a specific role in the cell

Summary

Introduction

X-linked dystonia–parkinsonism (XDP) is an adult-onset neurodegenerative movement disorder endemic to the Philippines, predominantly affecting men due to theX-linked mode of inheritance. In patients that survive this disease stage, parkinsonism sets in, overlaps with the dystonia, and predominates from the tenth year of illness onward [1,2]. More recent findings of reduced cortical thickness and cerebellar gray matter pathology implicate these additional regions in the pathogenesis of XDP [5]. All patients identified to date share a common haplotype, including the likely disease-causing variant, the SVA (SINE-VNTR-Alu) retrotransposon insertion in intron 32 of the TAF1 gene on the X chromosome [6,7,8,9,10]. Consistent with striatal degeneration, a neuron-specific TAF1 transcript is reduced in the caudate nucleus of XDP patients, as well as all TAF1 transcripts in various tissues and cell lines [7,9,10,11,12].

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