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A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies
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SYSNO ASEP 0499872 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies Tvůrce(i) Askeland, G. (NO)
Rodinová, M. (CZ)
Štufková, H. (CZ)
Dosoudilová, Z. (CZ)
Baxa, M. (CZ)
Šmatlíková, Petra (UZFG-Y) ORCID
Bohuslavová, Božena (UZFG-Y) ORCID
Klempíř, J. (CZ)
Nguyen, The Duong (UZFG-Y) ORCID
Kusnierczyk, A. (NO)
Bjoras, M. (NO)
Klungland, A. (NO)
Hansíková, H. (CZ)
Ellederová, Zdeňka (UZFG-Y) RID, ORCID
Eide, L. (NO)Číslo článku UNSP dmm035949 Zdroj.dok. Disease Models & Mechanisms. - : Company of Biologists - ISSN 1754-8403
Roč. 11, č. 10 (2018)Poč.str. 11 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova Huntington´s disease ; mitochondrial function ; DNA damage Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Cell biology CEP LO1609 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy 7F14308 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UZFG-Y - RVO:67985904 UT WOS 000448830700010 EID SCOPUS 85055595102 DOI 10.1242/dmm.035949 Anotace Huntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls. The TgHD minipigs showed progressive accumulation of the mutant huntingtin (mHTT) fragment in brain tissue and exhibited locomotor functional decline at 48 months. Interestingly, this neuropathology progressed without any significant age-dependent changes in any of the other biomarkers assessed. Rather, we observed genotype-specific effects on mitochondrial DNA (mtDNA) damage, mtDNA copy number, 8-oxoguanine DNA glycosylase activity and global level of the epigenetic marker 5-methylcytosine that we believe is indicative of a metabolic alteration that manifests in progressive neuropathology. Peripheral blood mononuclear cells (PBMCs) were relatively spared in the TgHD minipig, probably due to the lack of detectable mHTT. Our data demonstrate that neuropathology in the TgHD model has an age of onset of 48 months, and that oxidative damage and electron transport chain impairment represent later states of the disease that are not optimal for assessing interventions. Pracoviště Ústav živočišné fyziologie a genetiky Kontakt Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Rok sběru 2019
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