Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.11.086017v1?rss=1 Authors: Elorza, A., Marquez, Y., Cabrera, J. R., Sanchez-Trincado, J. L., Santos-Galindo, M., Hernandez, I. H., Diaz-Hernandez, J. I., Garcia-Escudero, R., Irimia, M., Lucas, J. J. Abstract: Deregulated alternative splicing has been implicated in a wide range of pathologies. Deep RNA-sequencing has revealed global mis-splicing signatures in multiple human diseases; however, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington's disease (HD) pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the HD-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked effector genes, whose aberrant splicing is associated with decreased protein levels in HD patients and mice. In summary, our intersect-RNA-seq approach unveiled the pathogenic contribution of mis-splicing to HD and could be readily applied to other neurodegenerative diseases for which bona fide animal models are available. Copy rights belong to original authors. Visit the link for more info