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

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, a

SUBMITTER: Tano V 

PROVIDER: S-EPMC10393612 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature