This title appears in the Scientific Report :
2018
Please use the identifier:
http://dx.doi.org/10.1021/acschemneuro.8b00027 in citations.
Please use the identifier: http://hdl.handle.net/2128/21119 in citations.
Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder
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...
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Personal Name(s): | Matthes, Frank |
---|---|
Massari, Serena / Bochicchio, Anna / Schorpp, Kenji / Schilling, Judith / Weber, Stephanie / Offermann, Nina / Desantis, Jenny / Wanker, Erich / Carloni, Paolo / Hadian, Kamyar / Tabarrini, Oriana (Corresponding author) / Rossetti, Giulia (Corresponding author) / Krauss, Sybille (Corresponding author) | |
Contributing Institute: |
Computational Biomedicine; INM-9 Jülich Supercomputing Center; JSC JARA - HPC; JARA-HPC Computational Biomedicine; IAS-5 |
Published in: | ACS chemical neuroscience, 9 (2018) 6, S. 1399 - 1408 |
Imprint: |
Washington, DC
ACS Publ.
2018
|
DOI: |
10.1021/acschemneuro.8b00027 |
PubMed ID: |
29506378 |
Document Type: |
Journal Article |
Research Program: |
Computational Science and Mathematical Methods Theory, modelling and simulation |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/21119 in citations.
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. |