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

作者：Zeng Li; Wang Bo; Merillat Sean A; Minakawa Eiko N; Perkins Matthew D; Ramani Biswarathan; Tallaksen Greene Sara J; Costa Maria do Carmo; Albin Roger L; Paulson Henry L^*

来源：Neurobiology of Disease, 2015, 82: 281-288.

DOI：10.1016/j.nbd.2015.06.017

• UBQLN2
• SCA3
• Huntington's disease
• Polyglutamine
• UBA
• UBL

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.

• 出版日期2015-10