Ubiquilin-2 differentially regulates polyglutamine disease proteins

Hum Mol Genet. 2020 Aug 29;29(15):2596-2610. doi: 10.1093/hmg/ddaa152.


Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins. Here we employ cellular models, primary neurons and mouse models to investigate the potential differential regulation by UBQLN2 of two polyglutamine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3). In cells, overexpressed UBQLN2 selectively lowered levels of full-length pathogenic HTT but not of HTT exon 1 fragment or full-length ATXN3. Consistent with these results, UBQLN2 specifically reduced accumulation of aggregated mutant HTT but not mutant ATXN3 in mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), respectively. Normally a cytoplasmic protein, UBQLN2 translocated to the nuclei of neurons in HD mice but not in SCA3 mice. Remarkably, instead of reducing the accumulation of nuclear mutant ATXN3, UBQLN2 induced an accumulation of cytoplasmic ATXN3 aggregates in neurons of SCA3 mice. Together these results reveal a selective action of UBQLN2 toward polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient to promote UBQLN2-mediated clearance of this class of disease proteins. Additional factors, including nuclear translocation of UBQLN2, may facilitate its action to clear intranuclear, aggregated disease proteins like HTT.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Ataxin-3 / genetics*
  • Autophagy-Related Proteins / genetics
  • Disease Models, Animal
  • Exons
  • Genetic Heterogeneity
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease / genetics*
  • Machado-Joseph Disease / genetics*
  • Mice
  • Neurons / metabolism
  • Neurons / pathology
  • Peptides / genetics
  • Proteasome Endopeptidase Complex


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Htt protein, mouse
  • Huntingtin Protein
  • Peptides
  • UBQLN2 protein, mouse
  • polyglutamine
  • Ataxin-3
  • Atxn3 protein, mouse
  • Proteasome Endopeptidase Complex