Abstract
Expression of mutant Huntingtin (HTT) protein is central to the pathophysiology of Huntington’s Disease (HD). The E3 ubiquitin ligase MID1 appears to have a key role in facilitating translation of the mutant HTT mRNA suggesting that interference with the function of this complex could be an attractive therapeutic approach. Here we describe a peptide that is able to disrupt the interaction between MID1 and the α4 protein, a regulatory subunit of protein phosphatase 2A (PP2A). By fusing this peptide to a sequence from the HIV-TAT protein we demonstrate that the peptide can disrupt the interaction within cells and show that this results in a decrease in levels of ribosomal S6 phosphorylation and HTT expression in cultures of cerebellar granule neurones derived from HdhQ111/Q7 mice. This data serves to validate this pathway and paves the way for the discovery of small molecule inhibitors of this interaction as potential therapies for HD.
Original language | English |
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Pages (from-to) | 44-50 |
Number of pages | 7 |
Journal | Neuroscience Letters |
Volume | 673 |
Early online date | 27 Feb 2018 |
DOIs | |
Publication status | Published - 23 Apr 2018 |
Keywords
- Huntington's Disease
- MID1
- Cerebellar granule cell culture