Journal Article

FZJ-2018-06523

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder

Matthes, F.FZJ* ; Massari, S. ; Bochicchio, A.FZJ* ; Schorpp, K. ; Schilling, J. ; Weber, S. ; Offermann, N. ; Desantis, J. ; Wanker, E. ; Carloni, P.FZJ* ; Hadian, K. ; Tabarrini, O. (Corresponding author) ; Rossetti, G. (Corresponding author)FZJ* ; Krauss, S. (Corresponding author)

2018
ACS Publ. Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/21119  doi:10.1021/acschemneuro.8b00027

Abstract: 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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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. JARA - HPC (JARA-HPC)
3. Jülich Supercomputing Center (JSC)
4. Computational Biomedicine (INM-9)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)
2. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)

Appears in the scientific report 2018

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Database coverage:
; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Free to read ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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