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Neuron. 2016 Nov 23;92(4):780-795. doi: 10.1016/j.neuron.2016.09.050. Epub 2016 Oct 20.

Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System.

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
4
Department of Biology, MIT, Cambridge, MA 02139, USA.
5
Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
6
Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
7
Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
9
Department of Molecular, Cell, and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
10
Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA 94107, USA.
11
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Molecular Engineering Laboratory, A(∗)STAR, Singapore 138673, Singapore. Electronic address: geneyeo@ucsd.edu.

Abstract

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.

PMID:
27773581
PMCID:
PMC5123850
DOI:
10.1016/j.neuron.2016.09.050
[Indexed for MEDLINE]
Free PMC Article

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