PRJNA666449
The incorporation of the neuron-specific microexon 34 of TAF1 is preserved in XDP brain tissues
X-linked Dystonia Parkinsonism (XDP) is a Mendelian inherited neurodegenerative disease, which manifests in the third and fourth decade of life. While the genetic cause of XDP has been identified as the retrotransposition of an SVA-F element into the TAF1 gene on the X-chromosome, the molecular basis of the disease is not clear. It has been proposed that XDP is caused by the decreased expression of a neuronal isoform of TAF1 mRNA, named TAF1-34, which would be due to the insertion of the SVA-F retrotransposon within intron 32 of TAF1. In this study, we demonstrate that the presence of the XDP-specific SVA does not preclude SRRM4-mediated microexon 34 incorporation into TAF1 mRNA in human cell systems. More importantly, assessment of microexon 34 incorporation in a comprehensive subset of different regions from eight XDP brains revealed the presence of microexon 34 within the TAF1 mRNA pool. Nanopore long-read sequencing confirmed that the exonic structure of TAF1 transcripts is preserved in XDP samples and showed a complex architecture of the TAF1 mRNA pool of control and XDP brains. Taken together, these data indicate that microexon 34 incorporation is not affected in the brains of XDP patients and that the presence of the XDP-specific SVA-F element does not impact the SRRM4-dependent splicing of this neuronal specific microexon. Our findings open new scenarios for the exploration of the molecular pathogenesis underlying XDP.