Re-establishing ataxin-2 downregulates translation of mutant ataxin-3 and alleviates Machado-Joseph disease

Brain. 2015 Dec;138(Pt 12):3537-54. doi: 10.1093/brain/awv298. Epub 2015 Oct 21.


Machado-Joseph disease is a progressive neurodegenerative disorder associated with the polyQ-expanded ataxin-3 (encoded by ATXN3), for which no therapy is available. With the aim of clarifying the mechanism of neurodegeneration, we hypothesized that the abnormally long polyQ tract would interact aberrantly with ataxin-2 (encoded by ATXN2), another polyQ protein whose function has recently been linked to translational regulation. Using patient's samples and cellular and animal's models we found that in Machado-Joseph disease: (i) ataxin-2 levels are reduced; and (ii) its subcellular localization is changed towards the nucleus. Restoring ataxin-2 levels by lentiviral-mediated overexpression: (i) reduced mutant ataxin-3 levels; and (ii) rescued behaviour defects and neuropathology in a transgenic mouse model of Machado-Joseph disease. Conversely (i) mutating the ataxin-2 motif that enables binding to its natural interactor and translation activator poly(A)-binding protein; or (ii) overexpressing poly(A)-binding protein, had opposite effects, increasing mutant ataxin-3 translation and aggregation. This work suggests that in Machado-Joseph disease, mutant ataxin-3 drives an abnormal reduction of ataxin-2 levels, which overactivates poly(A)-binding protein, increases translation of mutant ataxin-3 and other proteins and aggravates Machado-Joseph disease. Re-establishment of ataxin-2 levels reduces mutant ataxin-3 and alleviates Machado-Joseph disease pathogenesis opening a new avenue for therapeutic intervention in this and potentially other polyQ disorders.

Keywords: Machado-Joseph disease; PABP; ataxin-2; mutant ataxin-3; translation regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-2 / genetics*
  • Ataxin-2 / metabolism*
  • Ataxin-3 / biosynthesis
  • Ataxin-3 / genetics*
  • Down-Regulation*
  • Humans
  • Lentivirus / genetics
  • Machado-Joseph Disease / genetics*
  • Machado-Joseph Disease / metabolism*
  • Machado-Joseph Disease / therapy
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Poly(A)-Binding Proteins / metabolism
  • Protein Biosynthesis*


  • Ataxin-2
  • Poly(A)-Binding Proteins
  • Ataxin-3