Elorza, AinaraMárquez, YamileCabrera, JorgeSánchez-Trincado, José LuisSantos-Galindo, MaríaHernández, Ivó H.Picó, SaraDíaz-Hernández, Juan I.García-Escudero, RamónIrimia Martínez, ManuelLucas, José J.2021-05-142021-05-142021Elorza A, Márquez Y, Cabrera JR, Sánchez-Trincado JL, Santos-Galindo M, Hernández IH et al. Huntington's disease-specific mis-splicing unveils key effector genes and altered splicing factors. Brain. 2021;144(7):2009-23. DOI: 10.1093/brain/awab0870006-8950http://hdl.handle.net/10230/47561Correction of mis-splicing events is a growing therapeutic approach for neurological diseases such as spinal muscular atrophy or neuronal ceroid lipofuscinosis 7, which are caused by splicing-affecting mutations. Non-mutation harboring mis-spliced effector genes are also good candidate therapeutic targets in diseases with more complex etiologies such as cancer, autism, muscular dystrophies or neurodegenerative diseases. Next-generation RNA sequencing (RNA-seq) has boosted investigation of global mis-splicing in diseased tissue to identify such key pathogenic mis-spliced genes. Nevertheless, while analysis of tumour or dystrophic muscle biopsies can be informative on early stage pathogenic mis-splicing, 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 mis-spliced effector genes that -together with the deregulated splicing factors- become new possible therapeutic targets. In summary, here we report pathogenic global mis-splicing in HD striatum captured by our new intersect-RNA-seq approach that can be readily applied to other neurodegenerative diseases for which bona fide animal models are available.application/pdfeng© Ainara Elorza et al (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly citedCorea de Huntington (Malaltia)GenèticaProteïnesRNAinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1093/brain/awab087info:eu-repo/semantics/openAccess