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Ataxin-2 Regulates Translation in a New BAC-SCA2 Transgenic Mouse Model
Spinocerebellar ataxia type 2 (SCA2) is an inherited neurodegenerative disorder leading to predominant loss of Purkinje cells in the cerebellum and impairment of motor coordination. The mutation is expansion of a protein domain consisting of a stretch of glutamine amino acids. We generated a mouse model of SCA2 containing the entire human normal or mutant ATXN2 gene using bacterial artificial chromosome (BAC) technology. Mice expressing a BAC with 72 glutamines (BAC-Q72) developed a progressive cerebellar degeneration and motor impairment in contrast to mice carrying the normal human gene (BAC-Q22). We found that even prior to behavioral onset of disease, the abundance of specific messenger RNAs changed using deep RNA-sequencing. One of the mRNAs with early and significant changes was Rgs8. Levels of Rgs8 protein were even further reduced than mRNA levels in BAC-Q72 cerebella suggesting to us that mutant ATXN2 might have a role in mRNA stability and translation. Using a cellular model, we showed that the ATXN2 protein interacted with RGS8 mRNA and that this interaction differed between normal and mutant ATXN2. Presence of mutant ATXN2 resulted in reduced RGS8 protein translation in a cellular model. Our studies describe a mouse model of SCA2 expressing the entire human ATXN2 gene and emphasize the role of ATXN2 in mRNA metabolism.
Vyšlo v časopise: Ataxin-2 Regulates Translation in a New BAC-SCA2 Transgenic Mouse Model. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005182
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005182Souhrn
Spinocerebellar ataxia type 2 (SCA2) is an inherited neurodegenerative disorder leading to predominant loss of Purkinje cells in the cerebellum and impairment of motor coordination. The mutation is expansion of a protein domain consisting of a stretch of glutamine amino acids. We generated a mouse model of SCA2 containing the entire human normal or mutant ATXN2 gene using bacterial artificial chromosome (BAC) technology. Mice expressing a BAC with 72 glutamines (BAC-Q72) developed a progressive cerebellar degeneration and motor impairment in contrast to mice carrying the normal human gene (BAC-Q22). We found that even prior to behavioral onset of disease, the abundance of specific messenger RNAs changed using deep RNA-sequencing. One of the mRNAs with early and significant changes was Rgs8. Levels of Rgs8 protein were even further reduced than mRNA levels in BAC-Q72 cerebella suggesting to us that mutant ATXN2 might have a role in mRNA stability and translation. Using a cellular model, we showed that the ATXN2 protein interacted with RGS8 mRNA and that this interaction differed between normal and mutant ATXN2. Presence of mutant ATXN2 resulted in reduced RGS8 protein translation in a cellular model. Our studies describe a mouse model of SCA2 expressing the entire human ATXN2 gene and emphasize the role of ATXN2 in mRNA metabolism.
Zdroje
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