title: Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System.
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.
authors: 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.
authors: Fernando J
authors: FJ
authors: Martinez
authors: 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.
authors: Gabriel A
authors: GA
authors: Pratt
authors: 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.
authors: Eric L
authors: EL
authors: Van Nostrand
authors: 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.
authors: Ranjan
authors: R
authors: Batra
authors: 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.
authors: Stephanie C
authors: SC
authors: Huelga
authors: 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.
authors: Katannya
authors: K
authors: Kapeli
authors: Department of Biology, MIT, Cambridge, MA 02139, USA.
authors: Peter
authors: P
authors: Freese
authors: Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: Seung J
authors: SJ
authors: Chun
authors: Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: Karen
authors: K
authors: Ling
authors: 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.
authors: Chelsea
authors: C
authors: Gelboin-Burkhart
authors: 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.
authors: Layla
authors: L
authors: Fijany
authors: 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.
authors: Harrison C
authors: HC
authors: Wang
authors: 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.
authors: Julia K
authors: JK
authors: Nussbacher
authors: Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors: Sara M
authors: SM
authors: Broski
authors: Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Hong Joo
authors: HJ
authors: Kim
authors: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Rea
authors: R
authors: Lardelli
authors: 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.
authors: Balaji
authors: B
authors: Sundararaman
authors: Department of Molecular, Cell, and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: John P
authors: JP
authors: Donohue
authors: Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors: Ashkan
authors: A
authors: Javaherian
authors: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Jens
authors: J
authors: Lykke-Andersen
authors: 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.
authors: Steven
authors: S
authors: Finkbeiner
authors: Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: C Frank
authors: CF
authors: Bennett
authors: Department of Molecular, Cell, and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors: Manuel
authors: M
authors: Ares
authors: Department of Biology, MIT, Cambridge, MA 02139, USA.
authors: Christopher B
authors: CB
authors: Burge
authors: Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: J Paul
authors: JP
authors: Taylor
authors: Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: Frank
authors: F
authors: Rigo
authors: 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.
authors: Gene W
authors: GW
authors: Yeo
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D002470:Cell Survival / Q000235:genetics*; D003605:D-Amino-Acid Oxidase / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D026723:Polyadenylation; D021381:Protein Transport / Q000235:genetics*
chemical_list: D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D003605:D-Amino-Acid Oxidase