Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures. (23rd April 2018)

• Record Type: Journal Article
• Authors: Monteiro, Olivia; Chen, Changwei; Bingham, Ryan; Argyrou, Argyrides; Buxton, Rachel; Pancevac Jönsson, Christina; Jones, Emma; Bridges, Angela; Gatfield, Kelly; Krauß, Sybille; Lambert, Jeremy; Langston, Rosamund; Schweiger, Susann; Uings, Iain
• Is Part Of: Neuroscience letters. Volume 673(2018)
• Page Start: 44
• Page End: 50
• Publication Date: 2018-04-23
• Subjects: HTT Huntingtin -- HD Huntington's Disease -- MID1 Midline 1 -- PP2A Protein Phosphatase 2A -- mHTT Mutant Huntingtin -- wtHTT Wild type Huntingtin -- S6K 40S ribosomal S6 kinase -- mTOR Mammalian target of rapamycin -- CGN Cerebellar granule neurons -- MAP2 Microtubule Associated Protein 2 -- GFAP Glial Fibrillary Protein -- aCSF Artificial cerebral spinal fluid -- DIV Days in vitro; Huntington's disease -- MID1 -- Cerebellar granule cell culture; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2018.02.061
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Cerebellar granule neurons require nutrient replenishment to maintain expression of HTT in culture. Peptides derived from α4 disrupt the interaction between MID1 and α4. Disruption of the MID1 complex by peptides reduces pS6 and HTT expression in CGN 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 Hdh Q111/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.