Dataset Information

PolyQ-expanded ataxin-1 formed insoluble protein inclusions perturbing translation in a spinocerebellar ataxia type-1 model

ABSTRACT: Spinocerebellar ataxia type-1 is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1 protein. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are linked to neuronal death. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1. Using an inducible Sleeping Beauty transposon system, we overexpressed ATXN1Q82 gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects of the mutant protein. We characterized the structure and the protein composition of insoluble polyQ IIBs which gradually occupy the nuclei. In response to their formation, our transcriptome analysis reveals a cerebellum-specific perturbed protein interaction network, primarily affecting protein translation. Our study resolves the previously unknown architecture of insoluble polyQ IIBs and suggests that they affect the assembly and the function of the ribosome. Our inducible cell system faithfully models a human cerebellum at the end-stage of the disease.

INSTRUMENT(S): impact II

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Mesenchymal Stem Cell, Stem Cell

SUBMITTER: Kamil Mikulasek

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD012709 | Pride | 2020-02-18

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Petrakis_Mikulasek_LC_MS_Maxquant_txt.7z	Other
	Petrakis_Mikulasek_LC_MS_raw_data.d.7z	Other

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Publications

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

Laidou Stamatia S Alanis-Lobato Gregorio G Pribyl Jan J Raskó Tamás T Tichy Boris B Mikulasek Kamil K Tsagiopoulou Maria M Oppelt Jan J Kastrinaki Georgia G Lefaki Maria M Singh Manvendra M Singh Manvendra M Zink Annika A Chondrogianni Niki N Psomopoulos Fotis F Prigione Alessandro A Ivics Zoltán Z Pospisilova Sarka S Skladal Petr P Izsvák Zsuzsanna Z Andrade-Navarro Miguel A MA Petrakis Spyros S

Redox biology 20200211

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 e ...[more]

PMID: 32145456

Similar Datasets

Project description:A number of human neurodegenerative diseases result from the expansion of a glutamine repeat within the disease-causing protein. Spinocerebellar ataxia type1 is one such disease, caused by expansion of a polyglutamine tract in the novel protein ataxin-1. To faithfully model SCA1 in the mouse, we generated knock-in mice carrying 154 CAG repeats in the mouse Sca1 locus. These mice reproduced many aspects of the human disease. Despite ubiquitous expression of the mutant protein, they developed slowly progressive selective neurodegeneration , which is most distinct in Purkinje cells and spinal cord. Alterations in gene expression have been proposed to be involved in the pathogenesis of polyglutamine disease including SCA1, but the changes of gene expression in an authentic disease model have not been characterized. We believe that knowledge of these genes will give insight into the pathophysiology of SCA1 and may ultimately be relevant to the treatment of SCA1.,We will determine gene expression patterns in the cerebellum and forebrain at three different time points.,We propose that the genes whose expression is affected by mutant ataxin-1 expression are effectors for neuronal dysfunction and neuronal degeneration in the knock-in mice. We also hypothesize the difference in the expression levels of these genes accounts for selective vulnerability of neurons.,We will examine three time points: 4 weeks, 11 weeks, and 20 weeks of age. We have shown that the mice developed motor incoordination as revealed by rotating rod test as early as 5 weeks of age but it was not until 10 weeks that they start showing clear neurological phenotype such as clasping. At each point, we will compare the pattern between the mutant and wild-type littermate. Animals will be prepared and sacrificed by a standard procedure. Cerebellum and spinal cord are the most affected areas whereas forebrain shows less neurodegeneration. Tissue will be rapidly dissected from cerebellum and forebrain, frozen in liquid nitrogen, and stored at ?80 C until analysis. Tissues will be sent to the centers (as opposed to RNA). We will be providing 9 tissue samples from three litters for each time point to mitigate any expression differences resulting from subtle differences of procedure or environment where the mice grow.