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

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.

SUBMITTER: Elorza A

PROVIDER: S-EPMC8370404 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Elorza Ainara A Márquez Yamile Y Cabrera Jorge R JR Sánchez-Trincado José Luis JL Santos-Galindo María M Hernández Ivó H IH Picó Sara S Díaz-Hernández Juan I JI García-Escudero Ramón R Irimia Manuel M Lucas José J JJ

Brain : a journal of neurology 20210801 7

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. Mis-spliced effector genes that do not harbour mutations are also good candidate therapeutic targets in diseases with more complex aetiologies such as cancer, autism, muscular dystrophies or neurodegenerative diseases. Next-generation RNA sequencing (RNA-seq) has boosted investigation o ...[more]

PMID: 33725094

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

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

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