Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System
| Autor: | Gene W. Yeo, Manuel Ares, Katannya Kapeli, Seung J. Chun, Peter Freese, Harrison Wang, Hong Joo Kim, Stephanie C. Huelga, Rea M. Lardelli, Balaji Sundararaman, Sara Broski, Layla Fijany, Chelsea Gelboin-Burkhart, Frank Rigo, Jens Lykke-Andersen, Steven Finkbeiner, Ranjan Batra, J. Paul Taylor, Karen Ling, Eric L. Van Nostrand, Ashkan Javaherian, Christopher B. Burge, Fernando J. Martinez, C. Frank Bennett, Gabriel A. Pratt, Julia K. Nussbacher, John Paul Donohue |
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| Rok vydání: | 2016 |
| Předmět: |
D-Amino-Acid Oxidase
0301 basic medicine Polyadenylation Cell Survival Induced Pluripotent Stem Cells Fluorescent Antibody Technique Gene Expression RNA-binding protein Biology environment and public health Article Mice 03 medical and health sciences Exon Heterogeneous-Nuclear Ribonucleoprotein Group A-B Gene expression medicine Animals Humans Motor Neurons Gene Expression Profiling General Neuroscience Amyotrophic Lateral Sclerosis Alternative splicing Neurodegeneration RNA Fibroblasts medicine.disease Molecular biology Alternative Splicing Protein Transport 030104 developmental biology Case-Control Studies Mutation RNA splicing |
| Zdroj: | Neuron. 92:780-795 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2016.09.050 |
| Popis: | 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 ∼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. VIDEO ABSTRACT. |
| Databáze: | OpenAIRE |
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