Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS

Nat Neurosci. 2015 Aug;18(8):1175-82. doi: 10.1038/nn.4065. Epub 2015 Jul 20.


Increasing evidence suggests that defective RNA processing contributes to the development of amyotrophic lateral sclerosis (ALS). This may be especially true for ALS caused by a repeat expansion in C9orf72 (c9ALS), in which the accumulation of RNA foci and dipeptide-repeat proteins are expected to modify RNA metabolism. We report extensive alternative splicing (AS) and alternative polyadenylation (APA) defects in the cerebellum of c9ALS subjects (8,224 AS and 1,437 APA), including changes in ALS-associated genes (for example, ATXN2 and FUS), and in subjects with sporadic ALS (sALS; 2,229 AS and 716 APA). Furthermore, heterogeneous nuclear ribonucleoprotein H (hnRNPH) and other RNA-binding proteins are predicted to be potential regulators of cassette exon AS events in both c9ALS and sALS. Co-expression and gene-association network analyses of gene expression and AS data revealed divergent pathways associated with c9ALS and sALS.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Alternative Splicing
  • Amyotrophic Lateral Sclerosis / genetics*
  • C9orf72 Protein
  • Cerebellum / metabolism*
  • Frontal Lobe / metabolism*
  • Gene Expression Regulation / genetics*
  • Genetic Association Studies
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H / metabolism
  • Humans
  • Middle Aged
  • Polyadenylation / genetics
  • Proteins / genetics*
  • RNA / metabolism*
  • Sequence Analysis, RNA
  • Transcriptome / genetics*


  • C9orf72 Protein
  • C9orf72 protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H
  • Proteins
  • RNA

Supplementary concepts

  • Amyotrophic lateral sclerosis 1

Associated data

  • GEO/GSE67196