The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin

Neurobiol Dis. 2018 Jan;109(Pt A):127-136. doi: 10.1016/j.nbd.2017.10.002. Epub 2017 Oct 3.


Huntington's disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular pathways, including ubiquitin-dependent processes, by which mHTT is regulated remain incompletely understood. Ube2W is the only ubiquitin conjugating enzyme (E2) known to ubiquitinate substrates at their amino (N)-termini, likely favoring substrates with disordered N-termini. By virtue of its N-terminal polyQ domain, HTT has an intrinsically disordered amino terminus. In studies employing immortalized cells, primary neurons and a knock-in (KI) mouse model of HD, we tested the effect of Ube2W deficiency on mHTT levels, aggregation and neurotoxicity. In cultured cells, deficiency of Ube2W activity markedly decreases mHTT aggregate formation and increases the level of soluble monomers, while reducing mHTT-induced cytotoxicity. Consistent with this result, the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. This study sheds light on the potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in this polyQ neurodegenerative disease.

Keywords: Huntingtin; Huntington's disease; Neurodegeneration; Protein misfolding; Ube2W; Ubiquitin-conjugating enzyme; Ubiquitination.

MeSH terms

  • Animals
  • Corpus Striatum / enzymology
  • Corpus Striatum / pathology
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Huntingtin Protein / metabolism*
  • Huntington Disease / enzymology*
  • Huntington Disease / genetics
  • Inclusion Bodies / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / enzymology*
  • Neurons / pathology
  • Primary Cell Culture
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism*


  • Htt protein, mouse
  • Huntingtin Protein
  • UBE2W protein, mouse
  • Ubiquitin-Conjugating Enzymes