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.