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Body fluid exosomes as potential carriers of Huntington’s disease biomarkers
Kupcová Skalníková, Helena ; Červenka, Jakub ; Bohuslavová, Božena ; Turnovcová, Karolína ; Vodička, Petr
Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by a progressive motor, behavioural, and cognitive decline, ending in death. The cause of HD is an abnormal expansion of CAG repeats in HTT gene resulting in prolonged polyglutamine (polyQ) sequence in huntingtin protein (HTT). Huntingtin is a large protein (348 kDa) expressed ubiquitously through the body, with highest expression in the brain and testes. To study HD pathophysiology and to test experimental therapies, a transgenic HD minipig (TgHD) model expressing N-terminal part (N548-124Q) of human mutated huntingtin (mHTT) under the control of human huntingtin promoter was created in Libechov. Beside the mild neurological impairment, the TgHD boars show decreased fertility after 13th month of age.
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Stimulating autophagy and reducing inclusions in mouse model of Huntington's disease via expression of transcription factor EB (TFEB)
Vodička, Petr ; Chase, K. ; Iulliano, M. ; Tousley, A. ; Valentine, D. T. ; Sapp, E. ; Kegel-Gleason, K. B. ; Sena-Esteves, M. ; Aronin, N. ; DiFiglia, M.
Mutant huntingtin (mHTT) is encoded by the Huntington’s disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy. We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9.
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Mechanism of complex tooth shape development in reptiles
Landová, Marie ; Zahradníček, Oldřich ; Dosedělová, Hana ; Kavková, M. ; Zikmund, T. ; Buchtová, Marcela
Tooth shape formation in mammals is well known proces thanks to the broad studies on the mouse molars. The main role in regulation of this proces plays the enamel knot. Enamel knots are formed by cluster of cells, which serves as a source of numerous signalling molecules such as SHH or members of WNT, BMP and FGF families. Almost all our knowledge about teeth came from study on the mouse model. For better understanding of odontogenesis, it is however necessary to compare developmental processes to another species. One of the most heterogenic group of dentition type and shape are reptiles. How the shape of their teeth completed is still unknown. Aim of our study is therefore to uncover developmental processes involved in cusp formation in non-mammalian species with focus on reptiles. As model species for this study, we selected chameleons where multicuspis teeth develop in the caudal area of the jaw.
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Evaluation of efficacy and bio-distribution of AAV5-miHTT in HD minipig brain
Bohuslavová, Božena ; Juhás, Štefan ; Juhásová, Jana ; Ellederová, Zdeňka ; Motlík, Jan
Healthy minipigs (n=29) were pre-screened for serum AAV5 neutralizing antibodies (NABs) in serum by uniQure. Conclusions: Intrastriatal/intrathalamic bilateral application of AAV5-CAG-miHtt(3e13/1e13gctotal) or PBS/Sucrose (54μl/216μl) similarly to AA5-CAG-GFP didn´t cause any neurological deficit in transgenic as well as wild type animals. The body weight increased in all animals 84 days after AAV5-CAG-miHtt/PBS-Sucroseintrastriatal/intrathalamic delivery with two exceptions TGanimal L616 (AAV5-CAG-miHtt1e 13g ctotal) and WTanimal L485 (AAV5-CAG-miHtt3e13gc total). The TG boar N176 from group VII (PBS/Sucrose) died during narcosis 56 days after IP/IT application), shortly after CSF and blood collection.The boar breathed heavily and intermittently, then the heart stopped beat and resuscitation failed. We immediately flushed them by 20 L of PBS with heparin and collect all tissues. All animals had normal food consumption. Inflammatory proces in AAV5-CAG-miHtt (1e13 gc total) seems to be similar to PBS/Sucrose injected animals accompanied with no detectable histological pathologies.
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Phenotypic Analyses of the HD transgenic Minipig Model
Motlík, Jan ; Ellederová, Zdeňka
The transgenic model of Huntington’s disease in minipig (TgHD) was created in 2009 and information coding the sequence of N-terminal part of human mutated huntingtin was transferred to subsequent generations from both female and male sides. In each litter, transgenic (TgHD) and wild-type (WT) piglets were born in approximately equal ratio. At present, the Laboratory of Cell Regeneration and Plasticity keeps sets of animals in F2 and F3 generations with identical genetic background and bred in identical conditions of feeding and housing. The present research project was focused on a complex of non-invasive and invasive approaches to WT and TgHD minipigs to achieve the entire phenotypic analysis of HD progression in this large animal model.
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