Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures

Olivia Monteiro, Changwei Chen, Ryan Bingham, Argyrides Argyrou, Rachel Buxton, Christina Pancevac Jönsson, Emma Jones, Angela Bridges, Kelly Gatfield, Sybille Krauß, Jeremy Lambert, Rosamund Langston, Susann Schweiger, Iain Uings (Lead / Corresponding author)

Research output: Contribution to journalArticle

119 Downloads (Pure)

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 languageEnglish
Pages (from-to)44-50
Number of pages7
JournalNeuroscience Letters
Volume673
Early online date27 Feb 2018
DOIs
Publication statusPublished - 23 Apr 2018

Fingerprint

Huntington Disease
Pharmacology
Peptides
Human Immunodeficiency Virus Proteins
S 6
Protein Phosphatase 2
Ubiquitin-Protein Ligases
Mutant Proteins
Cell Communication
Phosphorylation
Neurons
Messenger RNA
Therapeutics
Proteins
Huntingtin Protein

Keywords

  • Huntington's Disease
  • MID1
  • Cerebellar granule cell culture

Cite this

Monteiro, Olivia ; Chen, Changwei ; Bingham, Ryan ; Argyrou, Argyrides ; Buxton, Rachel ; Jönsson, Christina Pancevac ; Jones, Emma ; Bridges, Angela ; Gatfield, Kelly ; Krauß, Sybille ; Lambert, Jeremy ; Langston, Rosamund ; Schweiger, Susann ; Uings, Iain. / Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures. In: Neuroscience Letters. 2018 ; Vol. 673. pp. 44-50.
@article{4638be681bc1408289d9c135e4667844,
title = "Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures",
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.",
keywords = "Huntington's Disease, MID1, Cerebellar granule cell culture",
author = "Olivia Monteiro and Changwei Chen and Ryan Bingham and Argyrides Argyrou and Rachel Buxton and J{\"o}nsson, {Christina Pancevac} and Emma Jones and Angela Bridges and Kelly Gatfield and Sybille Krau{\ss} and Jeremy Lambert and Rosamund Langston and Susann Schweiger and Iain Uings",
note = "This work was funded by GlaxoSmithKline as part of a collaboration between the University of Dundee and GSK under the Discovery Partnership with Academia Framework.",
year = "2018",
month = "4",
day = "23",
doi = "10.1016/j.neulet.2018.02.061",
language = "English",
volume = "673",
pages = "44--50",
journal = "Neuroscience Letters",
issn = "0304-3940",
publisher = "Elsevier",

}

Monteiro, O, Chen, C, Bingham, R, Argyrou, A, Buxton, R, Jönsson, CP, Jones, E, Bridges, A, Gatfield, K, Krauß, S, Lambert, J, Langston, R, Schweiger, S & Uings, I 2018, 'Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures', Neuroscience Letters, vol. 673, pp. 44-50. https://doi.org/10.1016/j.neulet.2018.02.061

Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures. / Monteiro, Olivia; Chen, Changwei; Bingham, Ryan; Argyrou, Argyrides; Buxton, Rachel; Jönsson, Christina Pancevac; Jones, Emma; Bridges, Angela; Gatfield, Kelly; Krauß, Sybille; Lambert, Jeremy; Langston, Rosamund; Schweiger, Susann; Uings, Iain (Lead / Corresponding author).

In: Neuroscience Letters, Vol. 673, 23.04.2018, p. 44-50.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures

AU - Monteiro, Olivia

AU - Chen, Changwei

AU - Bingham, Ryan

AU - Argyrou, Argyrides

AU - Buxton, Rachel

AU - Jönsson, Christina Pancevac

AU - Jones, Emma

AU - Bridges, Angela

AU - Gatfield, Kelly

AU - Krauß, Sybille

AU - Lambert, Jeremy

AU - Langston, Rosamund

AU - Schweiger, Susann

AU - Uings, Iain

N1 - This work was funded by GlaxoSmithKline as part of a collaboration between the University of Dundee and GSK under the Discovery Partnership with Academia Framework.

PY - 2018/4/23

Y1 - 2018/4/23

N2 - 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.

AB - 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.

KW - Huntington's Disease

KW - MID1

KW - Cerebellar granule cell culture

U2 - 10.1016/j.neulet.2018.02.061

DO - 10.1016/j.neulet.2018.02.061

M3 - Article

C2 - 29499308

VL - 673

SP - 44

EP - 50

JO - Neuroscience Letters

JF - Neuroscience Letters

SN - 0304-3940

ER -