Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors
| Autor: | Manuel Irimia, Ainara Elorza, José Luis Sánchez-Trincado, Ivó H. Hernández, Juan Ignacio Díaz-Hernández, Yamile Marquez, Jorge Rubén Cabrera, José J. Lucas, María Santos-Galindo, Ramón García-Escudero |
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| Jazyk: | angličtina |
| Předmět: |
0303 health sciences
Effector Alternative splicing RNA-Seq Computational biology Biology medicine.disease 03 medical and health sciences 0302 clinical medicine Huntington's disease Gliosis RNA splicing medicine medicine.symptom Gene 030217 neurology & neurosurgery Neuroinflammation 030304 developmental biology |
| Zdroj: | bioRxiv |
| DOI: | 10.1101/2020.05.11.086017 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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