RAN Translation in Huntington Disease

Neuron. 2015 Nov 18;88(4):667-77. doi: 10.1016/j.neuron.2015.10.038.


Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases.

Publication types

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

MeSH terms

  • Adult
  • Aged, 80 and over
  • Brain / metabolism*
  • Case-Control Studies
  • Cerebellum / metabolism
  • Child
  • Female
  • Frontal Lobe / metabolism
  • HEK293 Cells
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Male
  • Middle Aged
  • Neostriatum / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Peptides / metabolism
  • Protein Aggregation, Pathological / metabolism
  • Protein Biosynthesis
  • RNA, Antisense / genetics*
  • RNA, Antisense / metabolism
  • Trinucleotide Repeat Expansion / genetics*
  • Young Adult


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Peptides
  • RNA, Antisense
  • polyalanine
  • polyleucine
  • polyserine
  • polyglutamine
  • polycysteine