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Genes Dev., Jan 05 2024, | https://doi.org/10.1101/gad.351104.123
A mutation in the low-complexity domain of splicing factor hnRNPA1 linked to amyotrophic lateral sclerosis disrupts distinct neuronal RNA splicing networks
Yeon J. Lee 1,2 and Donald C. Rio 1,2,*
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA
2California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, California 94720, USA
*Corresponding author: correspondence to Donald C. Rio
Abstract
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in some ALS patients. Here, two human cell models were generated to investigate how a mutation in the C-terminal low-complexity domain (LCD) of hnRNPA1 can cause splicing changes of thousands of transcripts that collectively are linked to the DNA damage response, cilium organization, and translation. We show that the hnRNPA1 D262V mutant protein binds to new binding sites on differentially spliced transcripts from genes that are linked to ALS. We demonstrate that this ALS-linked hnRNPA1 mutation alters normal RNA-dependent protein-protein interactions. Furthermore, cells expressing this hnRNPA1 mutant exhibit a cell aggregation phenotype, markedly reduced growth rates, changes in stress granule kinetics, and aberrant growth of neuronal processes. This study provides insight into how a single amino acid mutation in a splicing factor can alter RNA splicing networks of genes linked to ALS.
논문정보
- Research article
- 2024년 01월 (BRIC 등록일 2024-01-10)
- 국외 연구진
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