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: Fernando J Martinez, Gabriel A Pratt, Eric L Van Nostrand, Ranjan Batra, Stephanie C Huelga, Katannya Kapeli, Peter Freese, Seung J Chun, Karen Ling, Chelsea Gelboin-Burkhart, Layla Fijany, Harrison C Wang, Julia K Nussbacher, Sara M Broski, Hong Joo Kim, Rea Lardelli, Balaji Sundararaman, John P Donohue, Ashkan Javaherian, Jens Lykke-Andersen, Steven Finkbeiner, C Frank Bennett, Manuel Ares Jr, Christopher B Burge, J Paul Taylor, Frank Rigo, Gene W Yeo
• Journal: Neuron (Neuron) Vol. 92 Issue 4 Pg. 780-795 (Nov 23 2016) ISSN: 1097-4199 [Electronic] United States
• PMID: 27773581 (Publication Type: Journal Article, Video-Audio Media)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Heterogeneous-Nuclear Ribonucleoprotein Group A-B
• D-Amino-Acid Oxidase

Topics

• Alternative Splicing (genetics)
• Amyotrophic Lateral Sclerosis (genetics, metabolism)
• Animals
• Case-Control Studies
• Cell Survival (genetics)
• D-Amino-Acid Oxidase (genetics, metabolism)
• Fibroblasts (metabolism)
• Fluorescent Antibody Technique
• Gene Expression
• Gene Expression Profiling
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B (genetics, metabolism)
• Humans
• Induced Pluripotent Stem Cells
• Mice
• Motor Neurons (metabolism)
• Mutation
• Polyadenylation
• Protein Transport (genetics)