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

Data de publicació electrònica: 16-03-2021Correction 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.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 M