Ubiquilin-2 differentially regulates polyglutamine disease proteins

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Polyglutamine expansion diseases exhibit diverse clinical and pathological features.
• Cellular proteostasis pathways, including the ubiquitin-proteasome system, handle disease-associated proteins differently.
• Ubiquilin-2 (UBQLN2) is a shuttle protein implicated in selective protein interactions within proteostasis networks.

Purpose of the Study:

• To investigate the differential regulation of huntingtin (HTT) and ataxin-3 (ATXN3) by UBQLN2 in polyglutamine expansion diseases.
• To elucidate the role of UBQLN2 in the cellular handling and aggregation of specific polyglutamine disease proteins.
• To explore the impact of UBQLN2's cellular localization on its therapeutic potential.

Main Methods:

• Utilized cellular models, primary neurons, and mouse models for Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3).
• Assessed the effect of overexpressed UBQLN2 on the levels and aggregation of full-length and fragmented HTT and ATXN3.
• Tracked the subcellular localization of UBQLN2 in response to pathogenic protein expression in neuronal models.

Main Results:

• Overexpressed UBQLN2 reduced full-length pathogenic HTT levels but not HTT exon 1 fragment or ATXN3 levels in cells.
• UBQLN2 decreased aggregated mutant HTT accumulation in HD mouse models but not aggregated mutant ATXN3 in SCA3 mouse models.
• UBQLN2 translocated to neuronal nuclei in HD mice, whereas in SCA3 mice, it induced cytoplasmic ATXN3 aggregate accumulation.

Conclusions:

• UBQLN2 exhibits selective action towards polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient for UBQLN2-mediated clearance.
• Factors such as UBQLN2's nuclear translocation may be crucial for its efficacy in clearing intranuclear aggregated proteins like HTT.
• The differential handling of HTT and ATXN3 by UBQLN2 highlights the complexity of proteostasis in polyglutamine diseases and suggests protein-specific therapeutic strategies.