Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/171690
Title: Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease
Authors: Tano, Vincent
Utami, Kagistia Hana
Nur Amirah Binte Mohammad Yusof
Bégin, Jocelyn
Tan, Willy Wei Li
Pouladi, Mahmoud A.
Langley, Sarah Raye
Keywords: Science::Medicine
Issue Date: 2023
Source: Tano, V., Utami, K. H., Nur Amirah Binte Mohammad Yusof, Bégin, J., Tan, W. W. L., Pouladi, M. A. & Langley, S. R. (2023). Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease. EBioMedicine, 94, 104720-. https://dx.doi.org/10.1016/j.ebiom.2023.104720
Project: RG23/22 
Journal: EBioMedicine 
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.
URI: https://hdl.handle.net/10356/171690
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2023.104720
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: Translational Laboratory in Genetic Medicine, A*STAR 
Rights: © 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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