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.

doi:http://dx.doi.org/10.1093/brain/awab087

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

Llicència

Citació

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

Resum

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.