期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04373-8
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资金
- Francis Crick Institute from Cancer Research UK [FC010110]
- UK Medical Research Council [FC010110]
- Wellcome Trust [FC010110, 101149/Z/13/A, 103760/Z/14/Z]
- MRC eMedLab Medical Bioinformatics Infrastructure Award [MR/L016311/1]
- UCL Grand Challenges Award
- Marie Curie Post-doctoral Research Fellowship [657749-NeuroUTR]
- Advanced Postdoc Mobility Fellowship from the Swiss National Science Foundation [P300PA_174461]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Wellcome Trust [101149/Z/13/A] Funding Source: Wellcome Trust
- MRC [MR/N020820/1, MR/M02492X/1] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [P300PA_174461] Funding Source: Swiss National Science Foundation (SNF)
Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS.
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