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The role of proteostatic mechanisms in neurodegenerative diseases
Zezulová, Kristýna ; Vodička, Petr (advisor) ; Marková, Vendula (referee)
Protein homeostasis (proteostasis) plays an important role in maintaining normal cell function and viability. Neurons are particularly vulnerable to proteostasis dysregulation, resulting in damage, dysfunction, and neuronal death, as manifested in many neurodegenerative diseases. One of them is Huntington disease, hereditary neurodegeneration with autosomal dominant inheritance. Expansion of the CAG repeats in the huntingtin gene is translated into an abnormally long glutamine chain in huntingtin protein, leading to disruption of neuronal proteostasis. The primary affected area of the brain is the striatum of the basal ganglia. Disease is progressive, the onset of symptoms usually occurs in adulthood, and after many years leads to the death of the patient. Despite intensive research, disease pathology is still not fully understood, treatment is still only symptomatic and new studies, together with a deeper understanding, also raise many new questions. Through the complexity of the issue, the study of proteostasis in neurodegeneration can bring not only possible implications for therapy, but also could go deeper into the understanding of stress, memory or aging processes.
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Protein quality control in the secretory pathway of eukaryotic cells
Bařinková, Markéta ; Stříšovský, Kvido (advisor) ; Černý, Jan (referee)
More than 30 % of the cellular proteome enters the secretory pathway during biogenesis in eukaryotic cells. The secretory pathway then ensures that these proteins are correctly folded, undergo necessary post- translational modifications, and reach their target site in membrane organelles or outside of the cell. Since a significant number of the nascent proteins in the pathway are or become dysfunctional, the cell must possess quality control mechanisms by which to weed them out. As proteins travel through the secretory pathway they may be degraded by various pathways in the endoplasmic reticulum, Golgi apparatus, endosomes, or at the plasma membrane. These degradatory pathways utilize a number of molecules including chaperones, ubiquitin ligases, and many others. They are coordinated by a unifying principle - the unfolded protein response, which acts as a support mechanism in case the degradation pathways are overwhelmed. The study of protein quality control mechanisms is necessary as they help us understand the production of a significant portion of the cellular proteome. Furthermore, defects in these degradation pathways are linked to several human diseases such as cystic fibrosis or some neurodegenerative diseases. These protein degradation pathways have been studied for decades, but thanks to...
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