Aberrant Splicing Exonizes Repeat Expansion in ALS/FTD

Overview

Journal bioRxiv

Date 2023 Nov 28

PMID 38014069

Authors

Suzhou Yang

Denethi Wijegunawardana

Udit Sheth

Austin M Veire

Juliana M S Salgado

Manasi Agrawal

Jeffrey Zhou

Joao D Pereira

Tania F Gendron

Junjie U Guo

Affiliations

Soon will be listed here.

Abstract

A nucleotide repeat expansion (NRE) in the first annotated intron of the gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5' splice sites and exported from the nucleus in a variety of spliced mRNA isoforms. aberrant splicing was substantially elevated in both C9 NRE motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.

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