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Retinitis pigmentosa-associated mutations in mouse Prpf8 cause misexpression of circRNAs and degeneration of cerebellar granule cells
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SYSNO ASEP 0571301 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Retinitis pigmentosa-associated mutations in mouse Prpf8 cause misexpression of circRNAs and degeneration of cerebellar granule cells Author(s) Krausová, Michaela (UMG-J) RID
Kreplová, Michaela (UMG-J)
Banik, Poulami (UMG-J)
Cvačková, Zuzana (UMG-J) RID
Kubovčiak, Jan (UMG-J)
Modrák, Martin (MBU-M) ORCID
Zudová, Dagmar (UMG-J)
Lindovský, Jiří (UMG-J) ORCID
Kubik-Zahorodna, Agnieszka (UMG-J)
Pálková, Marcela (UMG-J)
Kolář, Michal (UMG-J) RID, ORCID
Procházka, Jan (UMG-J) ORCID
Sedláček, Radislav (UMG-J) RID
Staněk, David (UMG-J) RIDNumber of authors 14 Article number e202201855 Source Title Life Science Alliance. - : Life Science Alliance
Roč. 6, č. 6 (2023)Number of pages 22 s. Language eng - English Country US - United States Keywords Prpf8 ; Retinitis pigmentosa ; circRNA ; cerebellar granule cells OECD category Biochemistry and molecular biology R&D Projects GA20-04099S GA ČR - Czech Science Foundation (CSF) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001789 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015861 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018131 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2015062 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001775 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 ; MBU-M - RVO:61388971 UT WOS 000968182500001 EID SCOPUS 85151803374 DOI 10.26508/lsa.202201855 Annotation A subset of patients with retinitis pigmentosa (RP) carry mutations in several spliceosomal components including the PRPF8 protein. Here, we established two alleles of murine Prpf8 that genocopy or mimic aberrant PRPF8 found in RP patients-the substitution p.Tyr2334Asn and an extended protein variant p.Glu2331ValfsX15. Homozygous mice expressing the aberrant Prpf8 variants developed within the first 2 mo progressive atrophy of the cerebellum because of extensive granule cell loss, whereas other cerebellar cells remained unaffected. We further show that a subset of circRNAs were deregulated in the cerebellum of both Prpf8-RP mouse strains. To identify potential risk factors that sensitize the cerebellum for Prpf8 mutations, we monitored the expression of several splicing proteins during the first 8 wk. We observed down-regulation of all selected splicing proteins in the WT cerebellum, which coincided with neurodegeneration onset. The decrease in splicing protein expression was further pronounced in mouse strains expressing mutated Prpf8. Collectively, we propose a model where physiological reduction in spliceosomal components during postnatal tissue maturation sensitizes cells to the expression of aberrant Prpf8 and the subsequent deregulation of circRNAs triggers neuronal death. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2024 Electronic address https://www.life-science-alliance.org/content/6/6/e202201855
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