Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease

Tano, Vincent, Utami, Kagistia Hana, Yusof, Nur Amirah Binte Mohammad, Bégin, Jocelyn, Tan, Willy Wei Li, Pouladi, Mahmoud A. and Langley, Sarah R. ORCID: https://orcid.org/0000-0003-4419-476X 2023. Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease. EBioMedicine 94 , 104720. 10.1016/j.ebiom.2023.104720

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Abstract

Background In Huntington's disease (HD), a CAG repeat expansion mutation in the Huntingtin (HTT) gene drives a gain-of-function toxicity that disrupts mRNA processing. Although dysregulation of gene splicing has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes in late-stage HD, limiting the ability to identify dysregulation related to early pathogenesis. Methods To investigate gene splicing changes in early HD, we performed alternative splicing analyses coupled with a proteogenomics approach to identify early CAG length-associated splicing changes in an established isogenic HD cell model. Findings We report widespread neuronal differentiation stage- and CAG length-dependent splicing changes, and find an enrichment of RNA processing, neuronal function, and epigenetic modification-related genes with mutant HTT-associated splicing. When integrated with a proteomics dataset, we identified several of these differential splicing events at the protein level. By comparing with human post-mortem and mouse model data, we identified common patterns of altered splicing from embryonic stem cells through to post-mortem striatal tissue. Interpretation We show that widespread splicing dysregulation in HD occurs in an early cell model of neuronal development. Importantly, we observe HD-associated splicing changes in our HD cell model that were also identified in human HD striatum and mouse model HD striatum, suggesting that splicing-associated pathogenesis possibly occurs early in neuronal development and persists to later stages of disease. Together, our results highlight splicing dysregulation in HD which may lead to disrupted neuronal function and neuropathology. Funding This research is supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Nanyang Assistant Professorship Start-Up Grant, the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 (RG23/22), the BC Children's Hospital Research Institute Investigator Grant Award (IGAP), and a Scholar Award from the Michael Smith Health Research BC.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Elsevier
ISSN:	2352-3964
Date of First Compliant Deposit:	17 August 2023
Date of Acceptance:	3 July 2023
Last Modified:	18 Aug 2023 02:59
URI:	https://orca.cardiff.ac.uk/id/eprint/161840

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