Background: Intracellular aggregation of polyglutamine (polyQ) proteins can be prevented by the chaperones DNAJB6 and DNAJB8. Results: DNAJB6 and DNAJB8 prevent the aggregation of pure polyQ peptides. Conclusion:The polyQ tract is sufficient for DNAJB6 and DNAJB8 to prevent aggregation. Significance: By interacting with polyQ fragments, DNAJB6 and DNAJB8 reduce polyQ protein aggregation and may be potential therapeutic targets in polyQ disorders.

Intracellular protein synthesis, folding, and degradation are tightly controlled processes to ensure proper protein homeostasis. The proteasome is responsible for the degradation of the majority of intracellular proteins, which are often targeted for degradation via polyubiquitination. However, the degradation rate of proteins is also affected by the capacity of proteasomes to recognize and degrade these substrate proteins. This capacity is regulated by a variety of proteasome modulations including (1) changes in complex composition, (2) post-translational modifications, and (3) altered transcription of proteasomal subunits and activators. Various diseases are linked to proteasome modulation and altered proteasome function. A better understanding of these modulations may offer new perspectives for therapeutic intervention. Here we present an overview of these three proteasome modulating mechanisms to give better insight into the diversity of proteasomes.

Background: Huntington disease is caused by an expanded polyglutamine repeat within the protein huntingtin. Results: Proteasomal degradation of mutant huntingtin fragments is devoid of polyglutamine peptides as partial cleavage products. Conclusion: Mammalian proteasomes are capable of entirely degrading expanded polyglutamine sequences. Significance: Accelerating the mutant huntingtin degradation by the proteasomal pathway obviates toxic species and represents a beneficial therapeutic strategy.