AI Article Synopsis
- A nucleotide repeat expansion (NRE) in the gene's first intron is linked to the most common genetic causes of ALS and FTD.
- Researchers discovered that C9 NRE-containing RNAs can undergo exonization and are exported from the nucleus as various spliced mRNA forms, with increased aberrant splicing observed in affected motor neurons and brain tissues.
- The findings suggest that NREs can trigger abnormal splicing, impacting the production and translation of RNAs, indicating a significant role in these neurodegenerative diseases.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680656 | PMC |
| http://dx.doi.org/10.1101/2023.11.13.566896 | DOI Listing |
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