Huntington's disease-specific mis-splicing unveils key effector genes and altered splicing factors

Elorza, Ainara; Márquez, Yamile; Cabrera, Jorge; Sánchez-Trincado, José Luis; Santos-Galindo, María; Hernández, Ivó H.; Picó, Sara; Díaz-Hernández, Juan I.; García-Escudero, Ramón; Irimia Martínez, Manuel; Lucas, José J.

Huntington's disease-specific mis-splicing unveils key effector genes and altered splicing factors

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dc.contributor.author Elorza, Ainara
dc.contributor.author Márquez, Yamile
dc.contributor.author Cabrera, Jorge
dc.contributor.author Sánchez-Trincado, José Luis
dc.contributor.author Santos-Galindo, María
dc.contributor.author Hernández, Ivó H.
dc.contributor.author Picó, Sara
dc.contributor.author Díaz-Hernández, Juan I.
dc.contributor.author García-Escudero, Ramón
dc.contributor.author Irimia Martínez, Manuel
dc.contributor.author Lucas, José J.
dc.date.accessioned 2021-05-14T07:25:06Z
dc.date.available 2021-05-14T07:25:06Z
dc.date.issued 2021
dc.description.abstract Correction 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.
dc.description.sponsorship grants PI2015-2/06-3 and PI2018/06-1 ; by grants : SAF2015-65371-R (MINECO/AEI/FEDER, UE) ; RTI2018-096322-B-I00 (MCIU/AEI/FEDER, UE) from Spanish Ministry of Economy and Competitiveness/Ministry of Science, Innovation and Universities (MINECO/MICINN) to JJL and BFU2017-89201-P (MINECO/AEI/FEDER, UE) to MI; PI18/00263 from the Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness) co-funded by the European Regional Development Fund- to RG-E; institutional grant from Fundación Ramón Areces to CBMSO ; Fundación BBVA to JJL; and by the European Research Council under the European Union's Horizon 2020 research and innovation program ERC-StG-LS2-637591 to MI
dc.format.mimetype application/pdf
dc.identifier.citation Elorza 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/awab087
dc.identifier.doi http://dx.doi.org/10.1093/brain/awab087
dc.identifier.issn 0006-8950
dc.identifier.uri http://hdl.handle.net/10230/47561
dc.language.iso eng
dc.publisher Oxford University Press
dc.relation.ispartof Brain. 2021;144(7):2009-23
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-65371-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89201-P
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/637591
dc.rights © 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 cited
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
dc.subject.other Corea de Huntington (Malaltia)
dc.subject.other Genètica
dc.subject.other Proteïnes
dc.subject.other RNA
dc.title Huntington's disease-specific mis-splicing unveils key effector genes and altered splicing factors
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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