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

J 2020

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

LAIDOU, Stamatia, Gregorio ALANIS-LOBATO, Jan PŘIBYL, Tamás RASKÓ, Boris TICHÝ et. al.

Basic information

Original name

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

Authors

LAIDOU, Stamatia, Gregorio ALANIS-LOBATO, Jan PŘIBYL (203 Czech Republic, belonging to the institution), Tamás RASKÓ, Boris TICHÝ (203 Czech Republic, belonging to the institution), Kamil MIKULÁŠEK (203 Czech Republic, belonging to the institution), Maria TSAGIOPOULOU, Jan OPPELT (203 Czech Republic, belonging to the institution), Georgia KASTRINAKI, Maria LEFAKI, Manvendra SINGH, Annika ZINK, Niki CHONDROGIANNI, Fotis PSOMOPOULOS, Alessandro PRIGIONE, Zoltan IVICS, Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution), Petr SKLÁDAL (203 Czech Republic, belonging to the institution), Zsuzsanna IZSVAK, Miguel A. ANDRADE-NAVARRO and Spyros PETRAKIS

Edition

Redox Biology, Amsterdam, Elsevier, 2020, 2213-2317

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

Netherlands

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 11.799

RIV identification code

RIV/00216224:14740/20:00116844

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1016/j.redox.2020.101458

UT WoS

000537459900001

Keywords in English

Ataxin-1; Polyglutamine; Sleeping beauty transposon; Oxidative stress; Protein network; Ribosome

Abstract

V originále

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.

Links

EF16_013/0001776, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii pro lidské zdraví

LM2018140, research and development project

Name: e-Infrastruktura CZ (Acronym: e-INFRA CZ)

Investor: Ministry of Education, Youth and Sports of the CR

692298, interní kód MU

Name: MEDGENET - Medical genomics and epigenomics network (Acronym: MEDGENET)

Investor: European Union, Spreading excellence and widening participation

90132, large research infrastructures

Name: NCMG II

Citovat

LAIDOU, Stamatia, Gregorio ALANIS-LOBATO, Jan PŘIBYL, Tamás RASKÓ, Boris TICHÝ, Kamil MIKULÁŠEK, Maria TSAGIOPOULOU, Jan OPPELT, Georgia KASTRINAKI, Maria LEFAKI, Manvendra SINGH, Annika ZINK, Niki CHONDROGIANNI, Fotis PSOMOPOULOS, Alessandro PRIGIONE, Zoltan IVICS, Šárka POSPÍŠILOVÁ, Petr SKLÁDAL, Zsuzsanna IZSVAK, Miguel A. ANDRADE-NAVARRO and Spyros PETRAKIS. Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery. Redox Biology. Amsterdam: Elsevier, 2020, vol. 32, MAY 2020, p. 1-16. ISSN 2213-2317. Available from: https://dx.doi.org/10.1016/j.redox.2020.101458.

@article{1689437,
   author = {Laidou, Stamatia and AlanisandLobato, Gregorio and Přibyl, Jan and Raskó, Tamás and Tichý, Boris and Mikulášek, Kamil and Tsagiopoulou, Maria and Oppelt, Jan and Kastrinaki, Georgia and Lefaki, Maria and Singh, Manvendra and Zink, Annika and Chondrogianni, Niki and Psomopoulos, Fotis and Prigione, Alessandro and Ivics, Zoltan and Pospíšilová, Šárka and Skládal, Petr and Izsvak, Zsuzsanna and AndradeandNavarro, Miguel A. and Petrakis, Spyros},
   article_location = {Amsterdam},
   article_number = {MAY 2020},
   doi = {http://dx.doi.org/10.1016/j.redox.2020.101458},
   keywords = {Ataxin-1; Polyglutamine; Sleeping beauty transposon; Oxidative stress; Protein network; Ribosome},
   language = {eng},
   issn = {2213-2317},
   journal = {Redox Biology},
   title = {Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery},
   url = {https://doi.org/10.1016/j.redox.2020.101458},
   volume = {32},
   year = {2020}
}

TY  - JOUR
ID  - 1689437
AU  - Laidou, Stamatia - Alanis-Lobato, Gregorio - Přibyl, Jan - Raskó, Tamás - Tichý, Boris - Mikulášek, Kamil - Tsagiopoulou, Maria - Oppelt, Jan - Kastrinaki, Georgia - Lefaki, Maria - Singh, Manvendra - Zink, Annika - Chondrogianni, Niki - Psomopoulos, Fotis - Prigione, Alessandro - Ivics, Zoltan - Pospíšilová, Šárka - Skládal, Petr - Izsvak, Zsuzsanna - Andrade-Navarro, Miguel A. - Petrakis, Spyros
PY  - 2020
TI  - Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery
JF  - Redox Biology
VL  - 32
IS  - MAY 2020
SP  - 1-16
EP  - 1-16
PB  - Elsevier
SN  - 22132317
KW  - Ataxin-1
KW  - Polyglutamine
KW  - Sleeping beauty transposon
KW  - Oxidative stress
KW  - Protein network
KW  - Ribosome
UR  - https://doi.org/10.1016/j.redox.2020.101458
L2  - https://doi.org/10.1016/j.redox.2020.101458
N2  - 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.
ER  -

LAIDOU, Stamatia, Gregorio ALANIS-LOBATO, Jan PŘIBYL, Tamás RASKÓ, Boris TICHÝ, Kamil MIKULÁŠEK, Maria TSAGIOPOULOU, Jan OPPELT, Georgia KASTRINAKI, Maria LEFAKI, Manvendra SINGH, Annika ZINK, Niki CHONDROGIANNI, Fotis PSOMOPOULOS, Alessandro PRIGIONE, Zoltan IVICS, Šárka POSPÍŠILOVÁ, Petr SKLÁDAL, Zsuzsanna IZSVAK, Miguel A. ANDRADE-NAVARRO and Spyros PETRAKIS. Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery. \textit{Redox Biology}. Amsterdam: Elsevier, 2020, vol.~32, MAY 2020, p.~1-16. ISSN~2213-2317. Available from: https://dx.doi.org/10.1016/j.redox.2020.101458.

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