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

S. Laidou, G. Alanis-Lobato, J. Pribyl, T. Raskó, B. Tichy, K. Mikulasek, M. Tsagiopoulou, J. Oppelt, G. Kastrinaki, M. Lefaki, M. Singh, A. Zink, N. Chondrogianni, F. Psomopoulos, A. Prigione, Z. Ivics, S. Pospisilova, P. Skladal, Z. Izsvák, MA....

. 2020 ; 32 (-) : 101458. [pub] 20200211

Language English Country Netherlands

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21020607

Spinocerebellar 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 protein synthesis. We propose that insoluble polyQ IIBs cause oxidative and nucleolar stress and affect the assembly of the ribosome by capturing or down-regulating essential components. The inducible cell system can be utilized to decipher the cellular consequences of polyQ protein aggregation. Our strategy provides a broadly applicable methodology for studying polyQ diseases.

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$a Spinocerebellar ataxia type-1 (SCA1) is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are somehow linked to neuronal death. However, owing to lack of a suitable cellular model, the downstream consequences of IIB formation are yet to be resolved. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1 and characterize IIB effects. Using an inducible Sleeping Beauty transposon system, we overexpressed the ATXN1(Q82) gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects caused by the expression of the mutant protein. We characterized the structure and the protein composition of insoluble polyQ IIBs which gradually occupy the nuclei and are responsible for the generation of reactive oxygen species. In response to their formation, our transcriptome analysis reveals a cerebellum-specific perturbed protein interaction network, primarily affecting protein synthesis. We propose that insoluble polyQ IIBs cause oxidative and nucleolar stress and affect the assembly of the ribosome by capturing or down-regulating essential components. The inducible cell system can be utilized to decipher the cellular consequences of polyQ protein aggregation. Our strategy provides a broadly applicable methodology for studying polyQ diseases.
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$a Alanis-Lobato, Gregorio $u Faculty of Biology, Johannes Gutenberg University Mainz, 55122, Mainz, Germany; Human Embryo and Stem Cell Laboratory, The Francis Crick Institute, NW1 1AT, London, UK
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$a Pribyl, Jan $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic
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$a Mikulasek, Kamil $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic; National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 62500, Brno, Czech Republic
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$a Tsagiopoulou, Maria $u Institute of Applied Biosciences/Centre for Research and Technology Hellas, 57001, Thessaloniki, Greece
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$a Oppelt, Jan $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic
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$a Kastrinaki, Georgia $u Aerosol and Particle Technology Laboratory/Chemical Process & Energy Resources Institute/Centre for Research and Technology Hellas, 57001, Thessaloniki, Greece
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$a Lefaki, Maria $u Institute of Biology, Medicinal Chemistry & Biotechnology/National Hellenic Research Foundation, 11365, Athens, Greece
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$a Singh, Manvendra $u Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany
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$a Zink, Annika $u Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University, 40225, Düsseldorf, Germany
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$a Chondrogianni, Niki $u Institute of Biology, Medicinal Chemistry & Biotechnology/National Hellenic Research Foundation, 11365, Athens, Greece
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$a Psomopoulos, Fotis $u Institute of Applied Biosciences/Centre for Research and Technology Hellas, 57001, Thessaloniki, Greece; Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177, Stockholm, Sweden
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$a Prigione, Alessandro $u Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University, 40225, Düsseldorf, Germany
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$a Ivics, Zoltán $u Division of Medical Biotechnology, Paul-Ehrlich-Institute, 63225, Langen, Germany
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$a Pospisilova, Sarka $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic
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$a Skladal, Petr $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic
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$a Izsvák, Zsuzsanna $u Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany. Electronic address: zizsvak@mdc-berlin.de
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$a Andrade-Navarro, Miguel A $u Faculty of Biology, Johannes Gutenberg University Mainz, 55122, Mainz, Germany
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$a Petrakis, Spyros $u Institute of Applied Biosciences/Centre for Research and Technology Hellas, 57001, Thessaloniki, Greece. Electronic address: spetrak@certh.gr
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