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

  • Expanded CAG trinucleotide repeats in Huntington’s disease (HD) are causative for neurotoxicity. The mutant CAG repeat RNA encodes neurotoxic polyglutamine proteins and 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 level of binding of HTT mRNA to MID1 and other target proteins in vitro. Metadynamics calculations, fairly consistent with experimental data measured here, provide hints about 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.

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Author:Frank MatthesORCiDGND, Serena Massari, Anna Bochicchio, Kenji Schorpp, Judith Schilling, Stephanie Weber, Nina Offermann, Jenny Desantis, Erich Wanker, Paolo Carloni, Kamyar Hadian, Oriana Tabarrini, Giulia Rossetti, Sybille Krauss
Frontdoor URL
Parent Title (English):ACS Chemical Neuroscience
Publisher:American Chemical Society (ACS)
Year of first Publication:2018
Publishing Institution:Universität Augsburg
Release Date:2023/11/23
Tag:Cell Biology; Cognitive Neuroscience; Physiology; Biochemistry; General Medicine
First Page:1399
Last Page:1408
Institutes:Medizinische Fakultät
Medizinische Fakultät / Professur für Physiologie (Meissner)
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):Sonstige Open-Access-Lizenz