TY - JOUR
T1 - Deregulated Splicing Is a Major Mechanism of RNA-Induced Toxicity in Huntington's Disease
AU - Schilling, Judith
AU - Broemer, Meike
AU - Atanassov, Ilian
AU - Duernberger, Yvonne
AU - Vorberg, Ina
AU - Dieterich, Christoph
AU - Dagane, Alina
AU - Dittmar, Gunnar
AU - Wanker, Erich
AU - van Roon-Mom, Willeke
AU - Winter, Jennifer
AU - Krauß, Sybille
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/4/19
Y1 - 2019/4/19
N2 - 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.
AB - 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.
KW - CAG repeat RNA
KW - RNA-binding proteins
KW - neurodegeneration
KW - polyglutamine disease
KW - spliceosome
UR - http://www.scopus.com/inward/record.url?scp=85061539453&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2019.01.034
DO - 10.1016/j.jmb.2019.01.034
M3 - Article
C2 - 30711541
AN - SCOPUS:85061539453
SN - 0022-2836
VL - 431
SP - 1869
EP - 1877
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 9
ER -