Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3

Neurobiol Dis. 2015 Oct;82:281-288. doi: 10.1016/j.nbd.2015.06.017. Epub 2015 Jun 30.


Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearance-related proteins into inclusions occur in many protein folding diseases, including polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissue of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), we show that UBQLN2 is selectively recruited to inclusions in HD but not SCA3. Consistent with this result, in a cell-based system mutant HTT interacts with UBQLN2 through the UBA domain while the SCA3 disease protein ATXN3, a deubiquitinating enzyme, does not interact with UBQLN2. Differential recruitment of UBQLN2 to aggregates in HD and SCA3 underscores the heterogeneity of inclusions in polyglutamine diseases and suggests that components of neuronal protein quality control may be differentially perturbed in distinct polyQ diseases.

Keywords: Huntington's disease; Polyglutamine; SCA3; UBA; UBL; UBQLN2.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Ataxin-3 / genetics
  • Ataxin-3 / metabolism
  • Autophagy-Related Proteins
  • Brain / metabolism*
  • Brain / pathology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • HEK293 Cells
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Intranuclear Inclusion Bodies / metabolism*
  • Intranuclear Inclusion Bodies / pathology
  • Machado-Joseph Disease / genetics
  • Machado-Joseph Disease / metabolism*
  • Machado-Joseph Disease / pathology
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Autophagy-Related Proteins
  • Cell Cycle Proteins
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Repressor Proteins
  • UBQLN2 protein, human
  • UBQLN2 protein, mouse
  • Ubiquitins
  • ATXN3 protein, human
  • Ataxin-3