Abstract
The Blm10/PA200 family of proteasome activators modulates the peptidase activity of the core particle (20S CP). They participate in opening the 20S CP gate, thus facilitating the degradation of unstructured proteins such as tau and Dnm1 in a ubiquitin- and ATP-independent manner. Furthermore, PA200 also participates in the degradation of acetylated histones. In our study, we use a combination of yeast and human cell systems to investigate the role of Blm10/PA200 in the degradation of N-terminal Huntingtin fragments (N-Htt). We demonstrate that the human PA200 binds to N-Htt. The loss of Blm10 in yeast or PA200 in human cells results in increased mutant N-Htt aggregate formation and elevated cellular toxicity. Furthermore, Blm10 in vitro accelerates the proteasomal degradation of soluble N-Htt. Collectively, our data suggest N-Htt as a new substrate for Blm10/PA200-proteasomes and point to new approaches in Huntington’s disease (HD) research.
Highlights
The fundamental cause of many neurodegenerative diseases is the formation of misfolded oligomers and aggregates, which eventually leads to cytotoxicity and cellular death [1]
We examined whether the loss of BLM10 affects the viability of yeast cells expressing Htt103Q, an exon1 fragment of huntingtin containing a stretch of 103 glutamines
A recent study demonstrated that the loss of PA200/Blm10 is the leading cause of the decline in proteasome activity during aging, which strengthens the idea that PA200/Blm10 might have a major role in age-related diseases
Summary
The fundamental cause of many neurodegenerative diseases is the formation of misfolded oligomers and aggregates, which eventually leads to cytotoxicity and cellular death [1]. In certain neurodegenerative diseases, such as Parkinson’s or Huntington’s disease, the genetic mutations, which are present in specific proteins (α-synuclein and huntingtin protein, respectively) can lead to the formation of larger oligomers and aggregates [5,6,7]. These aberrant proteins are quite resistant to degradation pathways. With aging and disease progression, the cellular proteostasis network becomes impaired and dysfunctional leading to cellular death [6]
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