期刊
NEURON
卷 92, 期 4, 页码 780-795出版社
CELL PRESS
DOI: 10.1016/j.neuron.2016.09.050
关键词
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资金
- National Science Foundation
- National Institute of General Medical Sciences of the NIH [T32GM008666]
- NIH [HG004659, NS075449, U54HG007005]
- California Institute of Regenerative Medicine [RB3-05009, RB4-06045]
- ALS Association [VC8K27]
- ALS Association
- Taube/Koret Center for Neurodegenerative Disease Research
HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within similar to 2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1.
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