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

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


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.

Publication types

  • Video-Audio Media

MeSH terms

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


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