Huntingtin protein: A new option for fixing the Huntington's disease countdown clock

Neuropharmacology. 2018 Jun;135:126-138. doi: 10.1016/j.neuropharm.2018.03.009. Epub 2018 Mar 8.


Huntington's disease is a dreadful, incurable disorder. It springs from the autosomal dominant mutation in the first exon of the HTT gene, which encodes for the huntingtin protein (HTT) and results in progressive neurodegeneration. Thus far, all the attempted approaches to tackle the mutant HTT-induced toxicity causing this disease have failed. The mutant protein comes with the aberrantly expanded poly-glutamine tract. It is primarily to blame for the build-up of β-amyloid-like HTT aggregates, deleterious once broadened beyond the critical ∼35-37 repeats threshold. Recent experimental findings have provided valuable information on the molecular basis underlying this HTT-driven neurodegeneration. These findings indicate that the poly-glutamine siding regions and many post-translation modifications either abet or counter the poly-glutamine tract. This review provides an overall, up-to-date insight into HTT biophysics and structural biology, particularly discussing novel pharmacological options to specifically target the mutated protein and thus inhibit its functions and toxicity.

Keywords: Aptamers; Biophysics; Huntingtin; Huntington's disease; Oligonucleotide.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Aptamers, Nucleotide / pharmacology*
  • Aptamers, Nucleotide / therapeutic use*
  • Humans
  • Huntingtin Protein / metabolism*
  • Huntington Disease / drug therapy*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Models, Molecular
  • Protein Processing, Post-Translational


  • Aptamers, Nucleotide
  • Huntingtin Protein