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Reducing mutant huntingtin protein expression in living cells by a newly identified RNA CAG binder

Item Type:Article
Title:Reducing mutant huntingtin protein expression in living cells by a newly identified RNA CAG binder
Creators Name:Matthes, F., Massari, S., Bochicchio, A., Schorpp, K., Schilling, J., Weber, S., Offermann, N., Desantis, J., Wanker, E.E., Carloni, P., Hadian, K., Tabarrini, O., Rossetti, G. and Krauss, S.
Abstract:Expanded CAG trinucleotide repeats in Huntington's disease (HD) are causative for neurotoxicity. Not only does the mutant CAG-repeat RNA encode for neurotoxic polyglutamine proteins, but also it can lead to a toxic gain-of-function by aberrantly recruiting RNA-binding proteins. One of these is the MID1 protein, which induces aberrant Huntingtin (HTT) protein translation upon binding. Here we have identified a set of CAG repeat binder candidates by in silico methods. One of those, furamidine, reduces the binding of HTT mRNA to MID1 and other target proteins in vitro. Metadynamics calculations, fairly consistent with experimental data measured here, provide hints on the binding mode of the ligand. Importantly, furamidine also decreases the protein level of HTT in a HD cell line model. This shows that small molecules masking RNA-MID1 interactions may be active against mutant HTT protein in living cells.
Keywords:Huntington's Disease, Metadynamics-Based Free Energy Calculations, Huntingtin Protein, Living Cell Experiments, Furamidine, RNA-MID1 Interactions
Source:ACS Chemical Neuroscience
Publisher:American Chemical Society
Page Range:1399-1408
Date:20 June 2018
Official Publication:https://doi.org/10.1021/acschemneuro.8b00027
PubMed:View item in PubMed

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