Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery

Publication date: Available online 11 February 2020Source: Redox BiologyAuthor(s): Stamatia Laidou, Gregorio Alanis-Lobato, Jan Pribyl, Tamás Raskó, Boris Tichy, Kamil Mikulasek, Maria Tsagiopoulou, Jan Oppelt, Georgia Kastrinaki, Maria Lefaki, Manvendra Singh, Annika Zink, Niki Chondrogianni, Fotis Psomopoulos, Alessandro Prigione, Zoltan Ivics, Sarka Pospisilova, Petr Skladal, Zsuzsanna Izsvák, Miguel A. Andrade-NavarroAbstractSpinocerebellar ataxia type-1 (SCA1) is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are somehow linked to neuronal death. However, owing to lack of a suitable cellular model, the downstream consequences of IIB formation are yet to be resolved. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1 and characterize IIB effects. Using an inducible Sleeping Beauty transposon system, we overexpressed the ATXN1(Q82) gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects caused by the expression of the mutant protein. We characterized the structure and the protein composition of insoluble polyQ IIBs which gradually occupy the nuclei and are responsible for the generation of reactive oxygen species. In response to their formation, our transcriptome analysis reveals a cerebellum-specific perturbed protein interaction network, primarily affecting pro...
Source: Redox Biology - Category: Biology Source Type: research