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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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Effects of NMDA receptor modulators on cell death in models of excitotoxicity in vitro.
Strnadová, Lenka ; Smejkalová, Tereza (advisor) ; Skřenková, Kristýna (referee)
NMDA receptors are ionotropic glutamate receptors (iGluR) activated by the amino acid glutamate and mediating signal transmission in the central nervous system. Their proper activity is essential for synaptogenesis, neuronal plasticity and synaptic transmission. However, excessive activation of NMDAR causes strong influx of calcium ions into neurons which triggers several destructive effects, eventually ending with cell death. This so-called excitotoxicity is present not only in many neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, but also in acute pathophysiological conditions, such as stroke or traumatic brain injury. General NMDAR inhibitors that could potentially prevent neuronal excitotoxicity have shown severe negative side effects in models in vivo. On the other hand, selective inhibitors of NMDA receptors with the ability to block the unwanted excessive activity while preserving NMDAR physiological function have shown to be therapeutically useful. This work is going to briefly summarize the knowledge of structure, activation and localization of NMDA receptors, then it is going to describe their rule in mediating neuronal toxicity and a few methods we can use to study excitotoxicity in vitro. Finally, this work will compare the effects of several known NMDAR...
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Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease
Červinková, Tereza ; Červený, Lukáš (advisor) ; Musílek, Kamil (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...
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The role of autophagy in neurodegenerative processes
Marková, Veronika ; Novotný, Jiří (advisor) ; Čermák, Vladimír (referee)
The characteristics of many neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's disease is the accumulation of proteins and damaged organelles in the cytoplasm. Unfortunately, they are not sufficiently eliminated by autophagy. The basal autophagy, that maintains the cellular homeostasis, is disturbed in neurodegeneration. The process of autophagy becomes saturated and unable to remove all the toxic substances. Therefore, other degradation mechanisms are activated, aiming to restore the homeostasis. However, the neuronal cells are damaged under certain conditions leading to their death. The reduction in the number of neurons in specific brain areas may cause severe ataxias and dementias. Better understanding of autophagocytosis and its role v pathogenesis of neurodegenerative diseases may contribute to more effective treatment of these serious diseases in the future. Key words: autophagy, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease
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EEG correlates of neurodegenerative disorders
Schlezingerová, Nicol ; Telenský, Petr (advisor) ; Kelemen, Eduard (referee)
Due to the aging of the population, there is an increasing incidence of neurodegenerative diseases. In clinical practice there is a need to for a cheap and noninvasive method for screening and early diagnosis of neurodegenerative disorders. To this end, markers of disease progression and prognosis must be determined. EEG correlates provide information that can be used in the diagnosis and prognosis of neurodegenerative disorders. Individual diseases have their specific EEG abnormalities that are closely related to different stages of the disease. Individual illnesses - Alzheimer's disease, Parkinson's disease, Huntington's disease have their specific changes in the basic rhythms of the brain that correlate with motor and cognitive changes. This work focuses on the quantitative (qEEG) correlates of the above-mentioned diseases. Key words: brain, neural activity, EEG, quantitative EEG analysis, biomarker, connectivity, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease.
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Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease
Červinková, Tereza ; Červený, Lukáš (advisor) ; Musílek, Kamil (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...
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Adenosine signaling: the role in neuroprotection and neurodegeneration
Hrušovská, Kateřina ; Novotný, Jiří (advisor) ; Kolář, David (referee)
The aim of this bachelor thesis is to describe basic and the most important mechanisms of adenosine signaling, especially in the central nervous system, where the purine nucleoside adenosine plays important role like significant neuromodulator. Strong release of adenosine to extracellular space may occur under some pathological conditions. Adenosine works throught his four receptors, which have very diverse functions. Some effects are neuroprotective - these are predominantly mediated throught the inhibitory A1 receptor, which can reduce neurotoxicity, others may also induce neurodegeneration, mainly due to increased activation of A2A receptors. This signaling system can be diversely modulated, for example by inhibition of enzymes, which can provide adenosine formation or degradation, blocking its transporters, by agonists or adenosine antagonists, or by inhibition of second messengers and various protein kinases by which adenosine affects cellular processes. Interactions of adenosine receptors with other types of receptors in the brain are also important. Adenosine and adenosine receptors can participate in neurodegenerative processes. A detailed understanding of the specific effects of adenosine can bring great progress in the treatment of neurodegenerative diseases. At present, intensive...
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Glutamate Receptors and Endoplasmic Reticulum Quality Control
Tachezy, Ruth ; Horák, Martin (advisor) ; Adámek, Pavel (referee)
Quality control (QC) is a collection of processes taking part in the biogenesis and architecture of proteins. The objective of this thesis is to describe these processes in detail. QC takes place on many different levels in various compartments of the cell. The focus is on the endoplasmic reticulum (ER) QC interconnected with cytosolic QC. There are multiple steps involved in ERQC: several types of protein translocation to the ER lumen, glycosylation, disulfide bond formation via protein disulfide isomerase, chaperones that assist to achieve a correct conformation, and ER- associated degradation pathway for retranslocation of misfolded proteins back to the cytoplasm, where they are degraded. Cytosolic QC is interconnected with the ERQC through various ways of translocation of proteins to the ER membrane or lumen. Proteins that are retranslocated from ER to the cytosol are ubiquitinated and subsequently degraded in the proteasome. Ubiquitination is a process of targeting a protein for degradation. Cytosolic chaperones and other cellular structures, such as aggresomes, juxtanuclear compartments, and insoluble protein deposits, take part in the ubiquitination. Calcium dysregulation that is linked to QC and correct protein folding in ER is also described. Some of the possible consequences of protein...
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