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@ARTICLE{Schilling:140674,
author = {Schilling, Judith and Broemer, Meike and Atanassov, Ilian
and Dürnberger, Yvonne and Vorberg, Ina and Dieterich,
Christoph and Dagane, Alina and Dittmar, Gunnar and Wanker,
Erich and van Roon-Mom, Willeke and Winter, Jennifer and
Krauß, Sybille},
title = {{D}eregulated {S}plicing {I}s a {M}ajor {M}echanism of
{RNA}-{I}nduced {T}oxicity in {H}untington's {D}isease.},
journal = {Journal of molecular biology},
volume = {431},
number = {9},
issn = {0022-2836},
address = {Amsterdam [u.a.]},
publisher = {Elsevier},
reportid = {DZNE-2020-06996},
pages = {1869-1877},
year = {2019},
abstract = {Huntington's disease (HD) is caused by an expanded CAG
repeat in the huntingtin (HTT) gene, translating into an
elongated polyglutamine stretch. In addition to the
neurotoxic mutant HTT protein, the mutant CAG repeat RNA can
exert toxic functions by trapping RNA-binding proteins.
While few examples of proteins that aberrantly bind to
mutant HTT RNA and execute abnormal function in conjunction
with the CAG repeat RNA have been described, an unbiased
approach to identify the interactome of mutant HTT RNA is
missing. Here, we describe the analysis of proteins that
preferentially bind mutant HTT RNA using a mass spectrometry
approach. We show that (I) the majority of proteins captured
by mutant HTT RNA belong to the spliceosome pathway, (II)
expression of mutant CAG repeat RNA induces mis-splicing in
a HD cell model, (III) overexpression of one of the splice
factors trapped by mutant HTT ameliorates the HD phenotype
in a fly model and (VI) deregulated splicing occurs in human
HD brain. Our data suggest that deregulated splicing is a
prominent mechanism of RNA-induced toxicity in HD.},
keywords = {Animals / Humans / Huntingtin Protein: genetics /
Huntington Disease: genetics / RNA: genetics / RNA Splicing:
genetics / Spliceosomes: genetics},
cin = {AG Krauß ; AG Krauß / AG Brömer 1 ; AG Brömer 1 / AG
Vorberg},
ddc = {610},
cid = {I:(DE-2719)1011006 / I:(DE-2719)5000021 /
I:(DE-2719)1013004},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342) / 341
- Molecular Signaling (POF3-341)},
pid = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-341},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30711541},
doi = {10.1016/j.jmb.2019.01.034},
url = {https://pub.dzne.de/record/140674},
}