Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease

Hum Mol Genet. 2016 Aug 15;25(16):3454-3466. doi: 10.1093/hmg/ddw187. Epub 2016 Jul 4.


Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the gene-encoding Huntingtin (HTT). Transcriptome dysregulation is a major feature of HD pathogenesis, as revealed by a large body of work on gene expression profiling of tissues from human HD patients and mouse models. These studies were primarily focused on transcriptional changes affecting steady-state overall gene expression levels using microarray based approaches. A major missing component, however, has been the study of transcriptome changes at the post-transcriptional level, such as alternative splicing. Alternative splicing is a critical mechanism for expanding regulatory and functional diversity from a limited number of genes, and is particularly complex in the mammalian brain. Here we carried out a deep RNA-seq analysis of the BA4 (Brodmann area 4) motor cortex from seven human HD brains and seven controls to systematically discover aberrant alternative splicing events and characterize potential associated splicing factors in HD. We identified 593 differential alternative splicing events between HD and control brains. Using two expanded panels with a total of 108 BA4 tissues from patients and controls, we identified four splicing factors exhibiting significantly altered expression levels in HD patient brains. Moreover, follow-up molecular analyses of one splicing factor PTBP1 revealed its impact on disease-associated splicing patterns in HD. Collectively, our data provide genomic evidence for widespread splicing dysregulation in HD brains, and suggest the role of aberrant alternative splicing in the pathogenesis of HD.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Alternative Splicing / genetics
  • Animals
  • Autopsy
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Heterogeneous-Nuclear Ribonucleoproteins / biosynthesis
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease / genetics*
  • Huntington Disease / physiopathology
  • Male
  • Mice
  • Middle Aged
  • Motor Cortex / metabolism*
  • Motor Cortex / pathology
  • Polypyrimidine Tract-Binding Protein / biosynthesis
  • Polypyrimidine Tract-Binding Protein / genetics*
  • Transcriptome / genetics*


  • Heterogeneous-Nuclear Ribonucleoproteins
  • Huntingtin Protein
  • PTBP1 protein, human
  • Polypyrimidine Tract-Binding Protein