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The impact of mutant huntingtin on oxidative stress in primary fibroblasts isolated from a new Huntington's disease knock in porcine model
Sekáč, Dávid ; Ellederová, Zdeňka (advisor) ; Hanzlíková, Hana (referee)
Huntington's chorea is a dominantly inherited disease caused by trinucleotide (Cytosine-Adenine -Guanine) expansion in a gene coding huntingtin protein. Carriers of these mutation show symptoms associated with motor impairment, a cognitive and psychiatric disturbance, which is called Huntington's disease (HD). The major sign of HD is striatal atrophy in the middle age of life. Since it is known that huntingtin protein participates in a lot of cellular processes, such as transcriptional regulation and metabolism, these processes change by its mutation. One of the features observed in HD pathogenesis is the presence of oxidative stress. The aim of the work was to monitor the molecular changes preceding the HD manifestation in the knock-in minipig model. As a material for monitoring molecular changes leading to this condition, primary fibroblasts were used. Whereas, the oxidative stress arises from an imbalance between oxidants and antioxidants, level of reactive species and lipid peroxidation together with expression of antioxidant response associated genes was measured. At the same time, expression of metabolic and DNA repair related genes was monitored. Although the differences in oxidative stress level or the expression of antioxidative response genes were not detected, the changes in the...
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Pathogenesis of Huntington's disease in peripheral tissues
Vachútová, Dominika ; Motlík, Jan (advisor) ; Fiala, Ondřej (referee)
Huntington's disease (HD) is an autosomal dominant inherited disorder with manifest of symptoms around the age of 40. This disorder is caused by an expansion of CAG repeats in huntingtin gene, Huntingtin (Htt) is a protein expressed in almost all tissues. HD is mainly characterized by neurodegeneration in the basal ganglia and cerebral cortex, but mutation in huntingtin have also serious influence on peripheral tissues. Many studies show serious heart dysfunction, weight loss, altered glucose homeostasis, impairment of energetic metabolism and muscular atrophy in HD patients and animal models. Till now, mechanism of these changes has not been sufficiently described and there is nor an adequate treatment yet. Key words: Huntington's disease, mutated huntingtin, CAG repeat, peripheral tissue
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The impact of mutant huntingtin on oxidative stress in primary fibroblasts isolated from a new Huntington's disease knock in porcine model
Sekáč, Dávid ; Ellederová, Zdeňka (advisor) ; Hanzlíková, Hana (referee)
Huntington's chorea is a dominantly inherited disease caused by trinucleotide (Cytosine-Adenine -Guanine) expansion in a gene coding huntingtin protein. Carriers of these mutation show symptoms associated with motor impairment, a cognitive and psychiatric disturbance, which is called Huntington's disease (HD). The major sign of HD is striatal atrophy in the middle age of life. Since it is known that huntingtin protein participates in a lot of cellular processes, such as transcriptional regulation and metabolism, these processes change by its mutation. One of the features observed in HD pathogenesis is the presence of oxidative stress. The aim of the work was to monitor the molecular changes preceding the HD manifestation in the knock-in minipig model. As a material for monitoring molecular changes leading to this condition, primary fibroblasts were used. Whereas, the oxidative stress arises from an imbalance between oxidants and antioxidants, level of reactive species and lipid peroxidation together with expression of antioxidant response associated genes was measured. At the same time, expression of metabolic and DNA repair related genes was monitored. Although the differences in oxidative stress level or the expression of antioxidative response genes were not detected, the changes in the...
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Gradual Molecular Changes in Primary Porcine Cells Expressing Mutated Huntingtin
Šmatlíková, Petra ; Motlík, Jan (advisor) ; Trejbalová, Kateřina (referee) ; Reiniš, Milan (referee)
Huntington's disease (HD) is inherited fatal disorder caused by CAG triplet expansions in the huntingtin gene resulting in the expression of mutated huntingtin protein (mtHtt). The main symptoms of HD are neurodegeneration, osteoporosis, testicular degeneration, loss of muscle tissue and heart muscle malfunction, weight loss, metabolic changes, and sleeping disturbances. Since huntingtin protein (Htt) has a role in several biological processes, many molecular mechanisms, like oxidative stress, mitochondrial dysfunction, DNA-damage, and others, are affected by mtHtt. However, its exact pathogenic mechanisms in HD are still not well understood. Transgenic minipig model of HD (TgHD) serves an opportunity to isolate unlimited number of primary cells and unlike primary cells obtained from HD patients, often in the late stages of the disease, the TgHD minipig model allows to monitor molecular changes occurring gradually with age and progression of the disease. Thus, TgHD minipig model and primary cells isolated from it play an important role in investigating and understanding the underlying mechanistic cause of HD. We focused on molecular and cellular changes in primary cells isolated from TgHD minipigs and their wild type (WT) controls at different ages (24, 36, and 48 months). In mesenchymal stem cells...
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Pathogenesis of Huntington's disease in peripheral tissues
Vachútová, Dominika ; Motlík, Jan (advisor) ; Fiala, Ondřej (referee)
Huntington's disease (HD) is an autosomal dominant inherited disorder with manifest of symptoms around the age of 40. This disorder is caused by an expansion of CAG repeats in huntingtin gene, Huntingtin (Htt) is a protein expressed in almost all tissues. HD is mainly characterized by neurodegeneration in the basal ganglia and cerebral cortex, but mutation in huntingtin have also serious influence on peripheral tissues. Many studies show serious heart dysfunction, weight loss, altered glucose homeostasis, impairment of energetic metabolism and muscular atrophy in HD patients and animal models. Till now, mechanism of these changes has not been sufficiently described and there is nor an adequate treatment yet. Key words: Huntington's disease, mutated huntingtin, CAG repeat, peripheral tissue
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