Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures
| Autor: | Rachel Buxton, Jeremy J. Lambert, Angela Bridges, Rosamund F. Langston, Argyrides Argyrou, Emma J. Jones, Christina Pancevac Jönsson, Susann Schweiger, Olivia Monteiro, Kelly M Gatfield, Changwei Chen, Ryan P. Bingham, Sybille Krauß, Iain Uings |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Huntingtin Mid1 protein mouse Protein subunit Ubiquitin-Protein Ligases Mutant Primary Cell Culture Peptide 03 medical and health sciences Mice Huntington's disease mental disorders medicine Animals Humans Htt protein mouse ddc:610 Protein Phosphatase 2 Neurons chemistry.chemical_classification Messenger RNA Huntingtin Protein biology Chemistry General Neuroscience Proteins genetics [Huntingtin Protein] metabolism [Protein Phosphatase 2] metabolism [Proteins] Protein phosphatase 2 medicine.disease Ubiquitin ligase Cell biology 030104 developmental biology HEK293 Cells metabolism [Neurons] metabolism [Huntingtin Protein] Mutation biology.protein Protein Binding |
| Zdroj: | Neuroscience letters 673, 44-50 (2018). doi:10.1016/j.neulet.2018.02.061 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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