TY  - JOUR
AU  - Matthes, Frank
AU  - Massari, Serena
AU  - Bochicchio, Anna
AU  - Schorpp, Kenji
AU  - Schilling, Judith
AU  - Weber, Stephanie
AU  - Offermann, Nina
AU  - Desantis, Jenny
AU  - Wanker, Erich
AU  - Carloni, Paolo
AU  - Hadian, Kamyar
AU  - Tabarrini, Oriana
AU  - Rossetti, Giulia
AU  - Krauss, Sybille
TI  - Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder
JO  - ACS chemical neuroscience
VL  - 9
IS  - 6
SN  - 1948-7193
CY  - Washington, DC
PB  - ACS Publ.
M1  - FZJ-2018-06523
SP  - 1399 - 1408
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29506378
UR  - <Go to ISI:>//WOS:000436211800022
DO  - DOI:10.1021/acschemneuro.8b00027
UR  - https://juser.fz-juelich.de/record/857532
ER  -