Aberrant splicing exonizes C9ORF72 repeat expansion in ALS/FTD.

Autor:	Yang S; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA., Wijegunawardana D; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA., Sheth U; Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences; Jacksonville, FL 32224, USA.; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Veire AM; Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences; Jacksonville, FL 32224, USA.; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Salgado JMS; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA., Agrawal M; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA., Zhou J; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA., Pereira JD; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA., Gendron TF; Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences; Jacksonville, FL 32224, USA.; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Guo JU; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA.; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06520, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 14. Date of Electronic Publication: 2023 Nov 14.
DOI:	10.1101/2023.11.13.566896
Abstrakt:	A nucleotide repeat expansion (NRE) in the first annotated intron of the C9ORF72 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. C9ORF72 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.
Databáze:	MEDLINE
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