Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8841586 | Neuroscience Letters | 2018 | 21 Pages |
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.
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Neuroscience (General)
Authors
Olivia Monteiro, Changwei Chen, Ryan Bingham, Argyrides Argyrou, Rachel Buxton, Christina Pancevac Jönsson, Emma Jones, Angela Bridges, Kelly Gatfield, Sybille KrauÃ, Jeremy Lambert, Rosamund Langston, Susann Schweiger, Iain Uings,