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1
Suxo, Blanco Macario. "Brucellosis in alpacas (Lama pacos) in communities of the city Ulla Ulla, Franz Tomayo province, department of La Paz." BYU ScholarsArchive, 2005. https://scholarsarchive.byu.edu/etd/5436.
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This investigation was performed in the Altiplano Altoandino sub-humid region in the Ulla Ulla district, Pelechuco township, Franz Tomayo province, department of La Paz, Bolivia. The objective of this study was to quantify and compare the presence of Brucellosis in male and female alpacas (Lama pacos) at ages 2, 3, 4, 5, 6, and 7 years. Blood samples were taken from the jugular vein of 500 alpacas from the Hichucollo, Huacuchani, Ucha Ucha, and Ulla Ulla communities. The serum from each sample was separated and a serological diagnosis was performed by rapid agglutination with Rose Bengal chemical stain. In the Ulla Ulla district, 11.0% of alpacas were suspected of being infected. Of that 11.0%, 9.6% represented female alpacas while the remaining 1.4% represented male alpacas. By community, the overall results were 0.6%, 0.2%, 7.4%, and 2.8% for Hichucollo, Huacuchani, Ucha Ucha, and Ulla Ulla respectively. With regards to gender in each community, 1.4%, 1.6%, 13.3%, and 11.1% of female alpacas and 2.7%, 0.0%, 1.2%, and 1.9 % of male alpacas were suspected of being infected in Hichucollo, Huacuchani, Ucha Ucha, and Ulla Ulla, respectively. According to age, 0.8%, 2.6%, 3.8%, 2.0%, 11.8%, and 0.0% were suspected of Brucellosis in alpacas 2, 3, 4, 5, 6, and 7 years old, respectively in the Ulla Ulla district. The analysis of variance among the results does not present significant differences (p ≥ 0.05), failing to reject the given hypothesis. The final prevalence point found in the Ulla Ulla district was 11.0%. It was concluded that the prevalence of suspected cases of Brucellosis in alpacas is a consequence of the antigenic characteristics of each biotype. Furthermore, the results affirm that the poor management of livestock and livestock health lead to significant problems with alpaca health. It is therefore necessary to implement control strategies as well as disease monitoring in communities by following a detailed program of diagnostic tests for Brucellosis. Also, non-infected flocks must be protected against infection.
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Moualla, Dima. "The role of alpha synuclein in Parkinson's disease." Thesis, University of Bath, 2011. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555747.
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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the presence of intracellular inclusions termed Lewy bodies (LBs) and Lewy neuritis (LNs) in the brain, in which α-Syn aggregates constitute the main component. Therefore, α-Syn aggregation was implicated in the pathogenesis of PD. Structurally α-Syn is a disordered protein with little ordered structure under physiological conditions. However, research of α-Syn has provided substantial information about its structural properties. The precise function of α-Syn is still under investigation. Research has also shown that metals, such as copper and iron, accelerate α-Syn aggregation and fibrillation in vitro and are proposed to play an important role in vitro. In this study, isothermal titration calorimetry was used to determine iron binding properties to α-Syn revealing the presence of two binding sites for iron with an affinity of 1.06 x 105 M-1 and a dissociation constant of ~ 10μM which is physiologically relevant to iron content in the brain. In addition, α-Syn was found to reduce iron in the presence of copper. This property was demonstrated via ferrozine based assay. In vitro, thoflavin-T fluorescence assay was used to investigate the mechanism by which metals induce α-Syn aggregation and whether it is related to metal binding. Metals, mainly copper and iron, caused 2-fold increase in the aggregation rate of WT α-Syn and its metal binding mutants. Linking that to the increased metal content in the brain, α-Syn aggregation can cause changes in tissue composition, thus altering the normal functional environment in the brain. Moreover, western blotting analysis showed that copper increases the aggregate formation in mammalian dopaminergic cells over-expressing α-Syn.
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VanHoy, Grace M. "Safety and serologic response to a Haemonchus contortus vaccine in alpacas." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1554827479078096.
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Gooptu, Bibekbrata. "Alpha₁-antichymotrypsin : conformational transitions and disease." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621614.
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Elliott, P. R. "Alpha-antitrypsin conformations in health and disease." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598809.
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Alpha1-antitrypsin is the most abundant proteinase inhibitor in plasma and the archetypal member of a large family of serine proteinase inhibitors known as the serpins. All serpin members have a common molecular architecture which consists of three β-sheets surrounded by eight α-helixes with an exposed mobile reactive centre loop. In this thesis I show that it is possible to induce and purify an inactive latent α1-antitrypsin conformation which can be reactivated after denaturation and refolding. An inactive latent component was also shown to exist in commercial α1-antitrypsin pasteurised for use as replacement therapy in patients with α1-antitrypsin deficiency. Another consequence of the mobile reactive centre loop is the formation of inactive loop-sheet polymers which form when the reactive centre loop of one molecule is inserted into the β-sheet of another. This interaction accounts for the retention of Z (Glu342→Lys) α1-antitrypsin in the endoplasmic reticulum of hepatocytes with accompanying plasma deficiency. I show here that the plasma deficiency associated with the common S α1-antitrypsin allele (Glu 264→Val), which is present in 19% of individuals of Spanish descent, can also be attributed to loop-sheet polymerisation. The structural basis of this loop-sheet linkage was clarified by the solving here of the crystal structures of intact wildtype and a thermostable mutant of α1-antitrypsin. Both structures show the reactive centre loop in a canonical conformation that docks perfectly with its cognate proteinase. The rest of the reactive centre loop is held in a β-strand conformation via a stabilising salt bridge with the body of the molecule. In this conformation the reactive loop can be readily modelled into the A β-sheet of a second molecule, providing strong support for A β-sheet linkage as the mechanism for loop-sheet polymerisation. Finally, loop-sheet polymers of α1-antitrypsin have also been shown to occur within the small airways and alveoli of the lungs of Z α1-antitrypsin homozygotes. This findings provides another mechanism for the inactivation of α1-antitrypsin, thereby exacerbating the proteinase-antiproteinase imbalance in the lung disease emphysema.
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Senior, Steven L. "Functional analysis of alpha-synuclein." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670161.
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Munishkina, Larissa. "[alpha]-synuclein, its properties and connection to protein deposition diseases /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2004. http://uclibs.org/PID/11984.
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Thakur, Garima. "Surface Chemistry and Spectroscopic Approach to Study Neurodegenerative Diseases." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/499.
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Accumulation or aggregation of amyloidogenic proteins in the brain plays a central role in neurodegenerative diseases. The most common and highly growing form of dementia in the elderly population is Alzheimer's disease (AD) followed by Parkinson's disease (PD). The major proteins associated are amyloid beta (Abeta) and alpha-synuclein (alpha-syn) in AD and PD, respectively. These proteins are released or found near the neuronal membranes in the brain. Consequently to understand the behavior of the proteins using a model membrane system becomes an important facet of understanding these diseases. Langmuir monolayer approach was used to study the surface chemistry and spectroscopy of Abeta (1-40), Abeta(1-42) and alpha-synuclein. Moreover, surface chemistry of a model protein namely, lysozyme was investigated. In recent times, quantum dots (QDs) are considered as potential probes for bio-imaging. These particles can be beneficial when it comes to the investigation of neurodegenerative diseases. The effect of nanoparticles, i.e., CdSe/ZnS QDs on Abeta (1-42) morphology was investigated. Nevertheless, it was observed that the capping ligand plays a significant role in the surface chemistry of QDs when mixed with or conjugated to Abeta (1-42). Surface pressure- and surface potential-area isotherms were used to characterize the lysozyme Langmuir monolayer. The compression-decompression cycles and stability measurements showed a homogeneous and stable monolayer at the air-water interface. Salt concentration in the subphase and pH of the subphase were parameters controlling homogeneity and stability of the Langmuir monolayer. In situ UV-vis and fluorescence spectroscopies were used to verify the homogeneity of the lysozyme monolayer, and to identify the chromophore residues in the lysozyme. Optimal experimental conditions were determined to prepare a homogeneous and stable lysozyme Langmuir monolayer. The surface chemistry and spectroscopy of the reduced lysozyme Langmuir monolayer were investigated at different pH values and were compared to a native lysozyme. It was established that the limiting molecular area of the reduced lysozyme was not subphase pH dependent as was found for the native one. To explain this result in terms of the conformation and orientation of the lysozyme Langmuir monolayer at various subphase pH values, we have used Infrared Reflection Absorption Spectroscopy (IRRAS). The interpretation of the results suggests a change in the conformation and orientation of the native lysozyme Langmuir monolayer with the subphase pH 3, 6 and 11. The surface chemistry of Abeta (1-40) and its interaction with the lipid raft Langmuir monolayer were examined where the stability of the lipid raft Langmuir monolayer came out as an essential parameter. Lipid raft Langmuir monolayer in the presence or absence of ganglioside GM1 having POPC as one of the phospholipids was found to be very unstable and collapsed within 26 min. Whereas, the phospholipid DPPG improved the stability of the monolayer significantly when cholesterol was used in excess. We have examined the surface and spectroscopic properties of Abeta (1-42) mixed with or conjugated to dihydrolipoic acid (DHLA)- and polyethylene glycol (PEG)- capped CdSe/ZnS QDs. Surface pressure-area isotherms, in situ UV-vis absorption, and fluorescence spectroscopy were used to characterize the Abeta (1-42) mixed with or conjugated to QDs at the air-water interface. The capping of QDs played a role in surface chemistry as was determined by surface pressure-area isotherms and spectroscopic properties of the Langmuir monolayer. Furthermore Abeta(1-42) was bioconjugated to DHLA-capped CdSe/ZnS QDs. Upon conjugation of Abeta (1-42) to DHLA-capped QDs, the sample was incubated at 37oC, the process of fibrillation was inhibited as compared with a sample where Abeta (1-42) was simply mixed with the QDs. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) were employed for the analysis of the samples. The morphology of fibrils and reduction in number of fibrils was substantial in the case of Abeta(1-42) conjugated to QDs. Reduction in fibrillation was also confirmed using a Thioflavin T assay. Moreover, quenching of tyrosine signal was observed in presence of the QDs, which indicates an interaction of QDs to the tyrosine residue in Abeta (1-42). The Surface chemistry and spectroscopy of alpha-syn, which is a natively unstructured protein important in the neuropathology of PD was investigated. IRRAS was utilized to investigate its conformation, alpha-syn was found to form a Langmuir monolayer in alpha-helical conformation with its helical axis parallel to the air-water interface.
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吳惠茵 and Wai-yan Ng. "Pokemon and pak interactive exchange factor alpha in gestational trophoblastic diseases." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40738322.
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Ng, Wai-yan. "Pokemon and pak interactive exchange factor alpha in gestational trophoblastic diseases." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40738322.
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Ettehadi, Parisa. "The role of tumour necrosis factor-alpha 9TNF-#alpha# and other cytokines in the celluar immunopathology of psoriasis." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266209.
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McWhinnie, Fergus Stewart. "Alpha synuclein in Parkinson's disease : determining the role of helical alpha synuclein using stapled peptides." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/29599.
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Neurodegeneration, the progressive and irrevocable loss of neuronal structure, is quickly becoming an imposing health concern in a globally ageing society. While specific neurodegenerative conditions exhibit specific clinical symptoms and progressions, a common neuropathological feature is the misfolding, oligomerisation and fibrillation of certain proteins causing neuronal stress and death. Parkinson’s disease, PD, has long been characterised by the death of nerve cells focused in the substantia nigra pars compacta region of the midbrain and deposition of large protein aggregates, called Lewy Bodies, throughout the central nervous system. More recently, the protein which forms these inclusion bodies was identified as alpha synuclein, αSyn, a ubiquitous neuroprotein with no known function. Furthermore, persons with mutations in the SNCA gene, which codes for αSyn, exhibit PD progression at a far younger age with a more severe phenotype, positively linking αSyn with PD. αSyn is an intrinsically disordered protein, IDP, and generally persists as such in solution and inside bacterial and mammalian cells. However, when in contact with a lipid bilayer the protein will embed upon the surface in an amphipathic alpha helical conformation and can also aggregate, forming toxic oligomeric and fibrillar species containing significant β-sheet identity. Its function as a helical apolipoprotein and subcellular localisation to both the nucleus and synapse has led researchers to suggest that αSyn has a role synaptic transmission and release. However, knocking out the protein does not reduce viability or produce pathological abnormalities in neuronal structure. The helical form of the protein may also persist as transient, metastable helical bundles which are non-toxic and resist aggregation. While a number of studies and tools have been reported and developed to investigate the toxic oligomeric/fibrillar forms of αSyn, very little attention has been accorded to the helical conformation. This thesis will redress this balance by producing tools which will allow us to mimic the helical form of αSyn, promote the active refolding of the full-length protein using a stable, helical peptide template and produce antibodies which recognise helical αSyn specifically for use in discovery and chaperone-like refolding. In Chapter 2 a region of αSyn (14 amino acids) was identified with a unique primary sequence located within a mutation prone section of the protein. Peptide ‘stapling’ technologies were then employed using a panel of monosubstituted ‘staple’ diastereomers, to produce a highly helical portion of αSyn. Using several other protein targets particular diastereomeric ‘staple’ combinations were analysed for obvious trends in helical content. Using solution NMR, backbone refined three dimensional structures of these helical peptides were produced which showed that they were faithful structural homologues of their parent helical proteins. In Chapter 3 the drug-like properties and therapeutic potential of stable, helical αSyn peptides were investigated. Using fluorescently labelled peptide substrates, ‘stapled’ peptides were shown to be far more cell penetrant than their wild type equivalents and demonstrated that the mechanism for cellular uptake appears to be specific. Furthermore, under harsh proteolytic conditions the ‘stapled’, helical peptides were far more resistant to hydrolysis than wild type or ‘stapled’, poorly helical peptides. The ‘stapled’ peptides were also highly soluble and did not appear to aggregate in a time-dependent manner. Using ion mobility mass spectrometry, it was shown that incubation of full-length protein with the ‘stapled’, helical peptides caused a contraction in the hydrodynamic radius of the protein. However, using solution NMR no active refolding of αSyn was observed when under the same conditions. Rather small perturbations in chemical shift were apparent which did not suggest that the αSyn protein folded into a discrete structural conformation, such as an alpha helix. In Chapter 4 the stable, helical αSyn peptide was employed as a conformational model and unique antigen in antibody discovery. Immunisation with the ‘stapled’, helical αSyn peptide initially produced a pool of polyclonal antibodies with a half log specificity for the helical peptide. After bespoke affinity chromatography this was increased to three log orders of specificity. Initial immunocytochemistry did not detect any helical αSyn protein in SH-SY5Y cells. To validate the helical epitope on the full-length protein in vitro an assay based around flow cytometry of synthetic vesicle structures was developed, with their synthesis, characterisation and binding of the αSyn protein described.
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Prager, Kai. "Investigation of #alpha#-secretase cleavage of amyloid precursor protein." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300994.
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Coburn, Leslie Ann. "Studies of platelet gpib-alpha and von willebrand factor bond formation under flow." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/39565.
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Understanding the differential bonding mechanics underlying bleeding disorders is of crucial importance to human health. In this research insight is provided into how four of these bleeding disorders (each with somewhat similar clinical characteristics), work at the molecular bond level. The bleeding diseases studied here can result from defects in the platelet glycoprotein (GP) Ibα the von Willebrand factor (vWF) molecule, or the ADAMTS-13 enzyme. Types 2B and 2M von Willebrand Disease (VWD) result in excess bleeding, yet type 2B has increased binding affinity between platelet GPIbα and vWF, while type 2M has decreased binding affinity between these two molecules. Platelet type VWD (pt-VWD) causes mutations in the GPIbα molecule and has similar characteristics to type 2B VWD. Further, in thrombotic thrombocytopenic purpura, bleeding results when there is a lack of active ADAMTS-13 enzyme. Each disease results in patient bleeding, but due to different mechanisms. This dissertation will explore the bonding mechanics between GPIbα and vWF and how they are altered in each disease state. To observe the GPIbα-vWF bonding mechanics, rolling velocities, transient tethering lifetimes, and tether frequency were determined using a parallel plate flow chamber. Data from these experiments suggest that wt-wt interactions are force dependent and have biphasic catch-slip bonding behavior. The data show that the shear stress at which the maximum mean stop time occurs differs between gain-of-function and loss-of-function mutations. Using similar methods, we study the changes resulting from pt-VWD mutations in GPIbα, and find that the catch bond seen for wt-wt interactions is lost for these mutations. Further, the data suggest that interactions with gain-of-function GPIbα mutations may be transport rather than force dependent. Finally, how the GPIbα-vWF tether bond changes for thrombotic thrombocytopenic purpura was also investigated to show that the bond lifetime in the absence of the enzyme is increased presenting a possible rationale for why bleeding occurs in this disease. Overall, the data show how the bonding mechanics of the GPIbα-vWF tether bond differ in four bleeding diseases. Further, these observations offer potential explanations for how these changes in the bonding mechanism may play a role in the observed patient bleeding.
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Hunn, Benjamin Henry Mcleod. "Macroautophagy, alpha-synuclein and dopamine neurotransmission : implications for Parkinson's disease." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:0b3161d2-bca3-49da-af63-a2cc7debaa84.
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Ghannad, Farzin. "Expression of alpha v beta 6 integrin in periodontal disease." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31758.
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Integrins are the principal cell surface receptors that mediate cell-to-cell or cell-to-extracellular matrix (ECM) binding, providing adhesion for stationary cells, traction
during cell movement and, importantly, translating extracellular matrix cues into
intracellular signal transduction pathways. The ανβ6 integrin, an exclusively epithelial
integrin, exhibits limited distribution in the body. In adult tissue, ανβ6 integrin is
expressed during inflammation, carcinogenesis, and in wound healing. It is not expressed
in oral gingival epithelium but it is constitutively expressed in junctional epithelium (JE).
Its capability to bind and activate transforming growth factor-β (TGFβ) suggests immune
regulation and it could therefore play a protective role against periodontal disease. When
comparing hematoxylin and eosin stained paraffin sections of wild-type (FVB) and β6
integrin-knockout mice (β6 -/-) under the light microscope, apical migration of junctional
epithelium beyond the cemento-enamel junction (CEJ) resulting in formation of pocket
epithelium (PE) was clearly demonstrated only in specimens of β6 integrin-knockout
animals. In addition, analysis of defleshed mandibles revealed a significant increase in
alveolar bone loss and therefore enhanced exposed root surface area and furcation
involvement for knockout mice in comparison to their age matched wild-type animals
(FVB). The findings of this study suggest that ανβ6 integrin, exclusively expressed in JE,
might play an important role in the pathogenesis of periodontal disease in mice. One
possible mechanism could be through its regulatory function in the activation of TGFβ.Dentistry, Faculty of
Graduate
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Flint, Nigel Stuart. "Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart." Master's thesis, University of Cape Town, 1985. http://hdl.handle.net/11427/26526.
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A recent proposal is that the alpha₁-adrenoceptor may mediate the arrhythmogenic effect of catecholamines during acute myocardial ischaernia. The purpose of this thesis was to explore the role of alpha₁ and alpha₂-adrenoceptor stimulation on vulnerability to ventricular fibrillation in the norrnoxic rat ventricular myocardium and further to evaluate the possible underlying cellular mechanism. The model used was the isolated perfused rat heart (Langendorff technique) in which ventricular fibrillation was electrically induced. The amount of current required to produce ventricular fibrillation was measured as the ventricular fibrillation threshold. Alpha₁-adrenoceptor stirnμlation with methoxamine to 10⁻⁶M to 10⁻⁵M increased the vulnerability to ventricular fibrillation. The arrhythmogenic effect of methoxamine could not be attributed to beta-adrenoceptor stimulation as it occurred in the setting of the beta-adrenoceptor antagonist agent, atenolol; furthermore no accumulation of cyclic AMP, the proposed arrhythmogenic second messenger of beta-adrenoceptor stimulation, occurred. Similarly no alteration in heart rate, coronary flow rate or myocardial high energy phosphate content accompanied the arrhythrnogenic effect of methoxamine. The QT interval increased with alpha₁-adrenoceptor stimulation, this being an indirect index of prolongation of the action potential duration. The arrhythmogenic action of methoxamine was associated with a positive inotropic effect. Prazosin 10⁻⁸M (an alpha₁-adrenoceptor antagonist agent) produced a tenfold displacement to the right of the log concentration response curve of the positive inotropic effect of methoxamine. Prazosin 10⁻⁸M prevented the methoxamine induced fall in ventricular fibrillation threshold. Alpha₂-adrenoceptor stimulation with B-HT 920 and B-HT 933 (azepexole), in the presence of the beta-adrenoceptor antagonist agent atenolol, did not alter the vulnerability to ventricular fibrillation. Alpha₂-adrenoceptor stimulation produced no alteration in heart rate, coronary flow rate or metabolic status. We next explored the possible mechanism underlying the arrhythmogenic effect of methoxamine. Alpha₁-adrenoceptor stimulation enhances transsarcolemmal calcium ion influx and may induce sarcoplasmic reticulum calcium release. To assess the role of transsarcolemmal calcium movement in alpha₁-adrenoceptor mediated effects experiments were undertaken with nisoldipine and low extracellular calcium. To evaluate the role of sarcoplasmic reticulum calcium release, experiments were undertaken with ryanodine (an agent reputed to inhibit sarcoplasmic reticulum calcium release without effecting the slow inward current). Nisoldipine 10⁻⁸M, reducing extracellular calcium (2.5 mM to 1.25 mM) and ryanodine 10⁻⁹M to 10⁻⁸M, prevented the arrhythmogenic and positive inotropic effect of methoxamine. Heart rate, metabolic status and cyclic AMP levels we're unchanged with these procedures. The mechanism underlying the arrhythmogenic action of alpha₁-adrenoceptor stimulation might be an increase in cytosolic calcium concentration. This increase may be secondary to (i) an enhanced transsarcolemmal calcium influx or (ii) an increase in the phasic release of calcium from the sarcoplasmic reticulum.
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Scott, Henry Hepburne. "#alpha#B-crystallin expression, mutagenesis and immunoreactivity." Thesis, University of Reading, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284449.
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Gowda, Vivek. "Potential interaction between LRRK2 and alpha synuclein drives dopaminergic neuron loss." Thesis, Boston University, 2013. https://hdl.handle.net/2144/21159.
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Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Parkinson’s Disease (PD) is a devastating progressive neurodegenerative disorder second only to Alzheimer's disease in prevalence. Progression is insidious and PD symptomology manifests when approximately half of the DA neurons projecting from the substantia nigra pars compacta (SNpc) to the striatum are lost. PD is histologically characterized by the presence of intracytoplasmic inclusions primarily composed of hyper-phosphorylated and ubiquinated α-synuclein (SNCA), known as Lewy Bodies. Conserved LB pathology in α-synuclein and LRRK2 mediated disease suggests a common pathological pathway in disease progression. In order to address the potential disease-relevant nexus between these two proteins, we generated transgenic C. elegans lines co-expressing LRRK2 (pan-neuronal) and α-synuclein (dopaminergic neuron specific). We report increased and progressive DA-ergic neuron loss in nematodes co-expressing disease linked mutant LRRK2 and α-synuclein compared to nematode lines expressing only α-synuclein. Also, guided by previous CLR network analysis, we implicated mis-regulation of proteostasis machinery in disease progression by demonstrating differential effects of LRRK2 co-expressed with α-synuclein on macroautophagy in our nematode lines expressing LGG, a marker for autophagic flux. Our studies show overexpression of G2019S LRRK2 inhibits autophagy and accelerates age-related dopaminergic neuron toxicity whereas overexpression of WT LRRK2 does not. Cooverexpression of a-synuclein caused increased inhibition of autophagy and showed an increase in DA-ergic neuron degeneration. Although we have no concrete evidence of interaction, we suggest that LRRK2 demonstrates an agedependent interaction with a-synuclein, which potentiates degeneration of dopaminergic neurons.
2031-01-01
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Brind, Alison Mary. "Alpha-1-antitrypsin granules in the liver." Thesis, University of Newcastle Upon Tyne, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309067.
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Dianda, Lee. "Immune responses in mice deficient in #alpha##beta# T cells." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244769.
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Mela, Marianna. "A pathogenic role for alpha-1-antitrypsin polymers in liver injury." Thesis, University of Cambridge, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709473.
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Guilliams, Tim Thomas. "Nanobodies as tools to gain insights into [alpha]-synuclein misfolding in Parkinson's disease." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608094.
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Marchese, Domenica 1986. "Post-transcriptional regulation of Alpha-synuclein and link to Parkinson's disease." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/525819.
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The role of RNA processing in the pathogenesis of neurodegenerative diseases is still poorly understood. α-synuclein (SNCA) is a presynaptic neuronal protein known as the major component of Lewy bodies, the pathological hallmark of Parkinson’s disease (PD). Recent evidence suggests a link between the pathogenesis of PD and the expression of SNCA mRNA isoforms with 3’ untranslated region (3’UTR) of different lengths. The purpose of my doctoral studies was the discovery of RNA-binding proteins (RBPs) regulating SNCA at the post-transcriptional level. Using computational and experimental approaches, I identified a number of trans-acting elements that physically interact with SNCA and potentially control its metabolism. I especially focused on the characterization of two RBPs, ELAVL1 and TIAR, and showed their implication in SNCA mRNA stability and translation efficiency. These two factors might play important roles in the maintenance of α-synuclein level and functionality in physiological and pathological conditions.Se sap ben poc sobre el paper del processament del RNA en la patogènesi de les malalties neurodegeneratives. L’α-sinucleïna (SNCA) és una proteïna neuronal presinàptica i el principal component dels cossos de Lewy, que al seu torn són la troballa patològica característica en la malaltia de Parkinson (MP). Recentment s’ha suggerit un lligam entre la patogènesi de la MP i l’expressió d’isoformes del mRNA de SNCA amb diferents longituds de les regions de 3’ no traduïdes (en anglès conegudes com a untranslated regions UTRs). El propòsit dels meus estudis de doctorat és descobrir les proteïnes que uneixen el RNA de SNCA i el regulen a nivell posttranscripcional. Gràcies a una combinació d’estratègies computacionals i experimentals he identificat elements que interaccionen físicament amb SNCA i potencialment en regulen el metabolisme actuant en trans. M’he centrat en la caracterització de dues proteïnes que uneixen RNA, ELAVL1 i TIAR, i mostro la seva implicació en la regulació de l’estabilitat del mRNA i l’eficiència en la seva traducció. Aquestes dues proteïnes podrien tenir un paper clau en el manteniment dels nivells de α-sinucleïna i la seva funció en condicions fisiològiques i patològiques.
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Chen, Lu-hua. "Evaluation of eIF-2 alpha phosphorylation in patients with Alzheimer's disease /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38284273.
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Belal, Cherine. "Mechanisms of alpha]-synuclein-induced neurodegenertaion in Parkinson's disease and stroke." Doctoral diss., University of Central Florida, 2011. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4745.
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Parkinson's disease (PD) is a debilitating neurodegenerative disorder affecting one million Americans. Despite its social and economic impact, the pathological cascades that lead to neuron dysfunction and degeneration in PD are poorly understood. Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases including PD. The ER is an organelle central to protein folding and intracellular Ca2+ homeostasis. Perturbations of these functions result in ER stress and upregulation of ER stress proteins, of which some have been implicated in counteracting ER stress-induced cell death. The mechanisms that lead to ER stress and how ER stress proteins contribute to the degenerative cascades remain unclear but their understanding is critical to devising effective therapies for PD. Both the accumulation of mutant a-synuclein (aSyn), which causes an inherited form of PD, and the inhibition of mitochondrial complex I function by PD-inducing neurotoxin lead to ER stress. The critical involvement of ER stress in experimental models of PD supports its potential relevance to PD pathogenesis and led us to test the hypothesis whether the homocysteine-inducible ER protein (Herp), an ubiquitin-like domain (UBD) containing ER-resident protein, can counteract mutant Alpha Syn- and neurotoxin- induced pathological cascades.ID: 031001465; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Title from PDF title page (viewed July 10, 2013).; Thesis (Ph.D.)--University of Central Florida, 2011.; Includes bibliographical references.
Ph.D.
Doctorate
Molecular Biology and Microbiology
Medicine
Biomedical Sciences
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Jamshidi, Yalda. "Role of PPAR#alpha# in coronary heart disease and cardiac hypertrophy." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252393.
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Senthilmohan, Tharmalingam. "The role of human alpha-2-macroglobulin in health and disease." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362274.
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Raaij, M. E. "Biophysical characterization of alpha-synuclein aggregated Parkinson's disease at the nanoscale /." Enschede : University of Twente [Host], 2008. http://doc.utwente.nl/60226.
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Piitulainen, Eeva. "Lung function in alpha1-antitrypsin deficiency register-based studies of its natural course and risk factors /." Malmö : Malmö University Hospital : Lund : Lund University, 1998. http://books.google.com/books?id=ZPprAAAAMAAJ.
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Elzouki, Abdul-Nasser. "Alpha₁-Antitrypsin deficiency (PiZ) clinical studies with special regard to hepatic and vasculitic disorders /." Malmö : Dept. of Medicine, University of Lund, University Hospital, 1998. http://catalog.hathitrust.org/api/volumes/oclc/39219467.html.
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Necula, Mihaela. "Tau and alpha-synuclein fibrillization in vitro lessons from surfactant inducers and small molecule inhibitors /." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1089239618.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains xix, 251p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 July 9.
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Swirski, Marta Izabella Hope. "Evaluating the relationship between alpha-synuclein phosphorylation and amyloid-beta in Lewy body diseases." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683554.
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Introduction: Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and a-synuclein (α-syn) accumulation. This thesis describes a series of studies exploring the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn) and at serine-87 (pSer87 α-synL in postmortem human brain tissue and in SH-SYSY neuroblastoma cells transfected to overexpress human α-syn. Methods: Formalin-fixed paraffin-embedded sections of cingulate and parahippocampal gyri from dementia with Lewy bodies (DLB), Parkinson's disease (PD) with dementia (PDD), Parkinson's disease without dementia (PDND) and control brains were immunolabelled for Aβ40, Aβ42, α-syn, pSer129 α-syn, and pSer87 α-syn. Levels of Aβ40, Aβ42, α-syn, and pSer129 α-syn, were also measured by sandwich ELlSA, in soluble and insoluble fractions of midfrontal, cingulate and para hippocampal cortex and thalamus, from cases of PDD, PDND, DLB and age-matched controls. The relationship of these measurements to cognitive decline was measured by time-to-dementia and the last available mini-mental state examination (MMSE) score in the PD patients with and without dementia, and to Braak tangle stage. Levels of α-syn, pSer129 α-syn and pSer87 α-syn were measured by sandwich ELlSA in SHSY-SY cells that had been stably transfected to over-express α-syn and were exposed to aggregated or soluble Aβ42 or Aβ40, at 1 or 10 μM. Results: Immunohistochemical data showed that Aβ42 and pSer129 α-syn antigen loads in the cingulate and parahippocampal cortex were higher in disease groups than controls, as measured by field fraction analysis. Significant positive correlations were observed between Aβ42 and pSer129 α-syn in both regions. In the cingulate cortex, the pSer87 α-syn field fraction was significantly lower in DLB than PDND, PDD or control brains. In the para hippocampal cortex, the pSer87 a-syn field fraction was significantly higher in PDD than PDND and DLB. Only in the midfrontal cortex was there a (positive) correlation between the pSer87 α-syn and Aβ42 field fractions. Data from sandwich ELlSAs showed that in most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak tangle stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SYSY cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect). Exposure of cells to 10 μM soluble or aggregated Aβ42 increased the percentage of insoluble α-syn that was phosphorylated at Ser87 but was not affected by treatment with Aβ40. Conclusions: Together these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and the Braak tangle stage, and predicts cognitive status in Lewy body diseases. In vitro, in the presence of Aβ42, phosphorylation of α-syn is also induced at Ser87. Phosphorylation at this latter site may be an initial protective response to increased Aβ42 in the human brain but, if so, it seems that the protective response fails as disease progresses
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Uemura, Norihito. "Viable neuronopathic Gaucher disease model in medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein." Kyoto University, 2015. http://hdl.handle.net/2433/200441.
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Morshed, Trisha. "THE RELATIONSHIP OF PLAQUES, TANGLES, AND LEWY‐TYPE ALPHA‐SYNUCLEINOPATHY TO VISUAL HALLUCINATIONS IN PARKINSON’S DISEASE AND ALZHEIMER’S DISEASE." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/535398.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Objective: Formed visual hallucinations are a common phenomenon in neurodegenerative disorders such as Parkinson’s Disease (PD), Alzheimer’s disease (AD) and Dementia with Lewy bodies (DLB). While Lewy‐type alpha‐synucleinopathy (LTSis the hallmark neuropathological finding in PD and DLB, amyloid plaques and neurofibrillary tangles are the pathological finding in AD. Previous research has linked complex or formed visual hallucinations (VH) to LTS in neocortical and limbic areas in patients with PD and DLB. As VH also occur in Alzheimer’s disease, and AD pathology often co‐occurs with LTS, we questioned whether this pathology might also be linked to VH. Methods: We performed a semi‐quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson’s disease (PD), Alzheimer’s disease (AD), or dementia with Lewy bodies (DLB). 173 subjects – including 50 with VH and 123 without VH – were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini‐mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities. Results: A significant relationship was found between the density of LTS and the presence of VH in all diagnostic groups. Plaque and tangle densities also were associated with VH in PD (p=.003 for plaque and p=.004 for tangles), but not in AD, where densities were high regardless of the presence of hallucinations.. Conclusion: Plaques and tangles as well as LTS may contribute to the pathogenesis of VH. Incident VH may be a clinical indicator of underlying pathological events: the development of plaques and tangles in patients with PD, and LTS in patients with AD.
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Clinkenbeard, Erica Leigh. "INSIGHTS INTO HEPATIC ALPHA-FETOPROTEIN GENE REGULATION DURING LIVER DEVELOPMENT AND DISEASE." UKnowledge, 2012. http://uknowledge.uky.edu/microbio_etds/1.
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The liver is an essential organ for cholesterol homeostasis. If this process becomes dysregulated, cardiovascular disease (CVD) develops. Zinc-fingers and homeoboxes 2 (Zhx2) as an important hepatic gene regulator and contributes to CVD. BALB/cJ mice, with mutant Zhx2 allele, have fewer atherosclerotic plaques compared to other strains on a high fat diet. In my dissertation, I focused on the liver phenotype in BALB/cJ mice on a high-fat diet and found increased liver damage compared to wild-type Zhx2 mice. These data indicates that reduced Zhx2 in the liver leads to CVD resistance, but increases liver damage. Therefore, Zhx2 has an important role in lipid metabolism and liver function.
Hepatic alpha-fetoprotein (AFP) is expressed abundantly in the fetal liver and repressed after birth regulated through three enhancers (E1, E2, and E3). E3 activity is restricted to a single layer of hepatocytes surrounding central veins (pericentral region) along with glutamine synthetase (GS). In my dissertation, I explore pericentral gene regulation in the adult liver. A GS enhancer (GSe) also exhibits pericentral activity which, along with E3, is regulated by the β-catenin signaling pathway. Orphan receptors, Rev-erbα, Rev-erbβ, and RORα, contribute to E3 activity elucidating a potential mechanism for zonation.
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Illes-Toth, Timea E. "Linking the structure of alpha-synuclein oligmers to function in Parkinson's disease." Thesis, Sheffield Hallam University, 2013. http://shura.shu.ac.uk/19857/.
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Misfolding and aggregation of alpha-synuclein (a-syn) are associated with a range of neurological disorders, including Parkinson's disease (PD). Fibrillar, insoluble aggregates of a-syn, known as Lewy bodies (LBs) are deposited in the substantia nigra and are a pathological hallmark of PD. a-syn is a natively unstructured protein, co-populating extended and more compact conformational forms under equilibrium. The fine balance of this equilibrium can be shifted due to changes in its environment such as alterations in metal content, ionic strength, free dopamine or others, promoting the assembly of a-syn into toxic conformations. Small, soluble oligomers preceding LB formation are thought to be causative, in vitro, different a-syn oligomers have been produced with alternate biochemical properties. Here the primary objective was to uncover the link between conformation and toxic gain of function by the use of functional assays in combination with ESI-IMS-MS. Epitope mapping procedures indicated that different a-syn oligomers have unique epitope features. Dye binding assays such as ThT and ANS fluorescence inferred that the various oligomer types differ in their amyloidogenicity and hydrophobicity. Furthermore, intracellular aggregation assays, MTT cell proliferation and Ca(ll) influx analysis in SH-SY5Y neuroblastoma cells showed that cellular effects correlated with structural features. ESI-IMS-MS spectra of the different oligomers have been acquired and allowed the conformations of the oligomer subsets to be determined. The oligomers assembled up to a hexameric form with a closed ring-like conformation. These results demonstrated that unique structural features are required for toxicity and that a subset of oligomers with characteristic structures may be pivotal in PD.
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Roberts, Rosalind F. "The role of alpha-synuclein oligomers in Parkinson's disease pathophysiology and biology." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:e13d9429-f2cd-4764-bf8d-d139e71f7711.
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Accumulating evidence links oligomeric species of the protein alpha-synuclein to the neuronal death associated with Parkinson's disease. However, the direct detection of alpha-synuclein oligomers in post-mortem brain has been challenging and this has limited our understanding of their structure, distribution and effects in Parkinson's disease. The work presented in this thesis addresses two aspects of the role of alpha-synuclein oligomers in Parkinson's disease. Firstly, I describe the development of a novel technique, the alpha-synuclein proximity ligation assay (AS-PLA), which specifically detected alpha-synuclein oligomers in vitro and in post-mortem brain tissue. In a blinded study with post-mortem brain tissue from eight Parkinson's disease patients and eight controls, AS-PLA revealed widespread, previously unrecognised pathology in the form of extensive diffuse deposition of alpha-synuclein oligomers. Furthermore, AS-PLA preferentially detected early-stage, loosely compacted Parkinson's disease lesions such as pale bodies, whereas Lewy bodies, considered heavily compacted late lesions were only very exceptionally stained. The oligomeric species detected by AS-PLA displayed a unique, intermediate proteinase K resistance profile, suggesting the detection of a conformer that is different from both physiological pre-synaptic alpha-synuclein (proteinase K sensitive) and highly aggregated alpha-synuclein within Lewy bodies (proteinase K resistant). In addition, AS-PLA revealed the age-dependent accumulation of alpha-synuclein oligomers in the substantia nigra of a BAC transgenic mouse model of Parkinson's disease that overexpresses human wild-type alpha-synuclein, SNCA-OVX. Secondly, the detection of early pathology in Parkinson's disease brain tissue using AS-PLA suggests that oligomeric species of alpha-synuclein could represent a potential target for therapeutic intervention. Therefore, I undertook a screen to identify compounds that can prevent the formation of alpha-synuclein oligomers in vitro. Using bimolecular fluorescence complementation constructs, I identified nine compounds capable of reducing the fluorescence indicative of the formation of alpha-synuclein oligomers. Two of these compounds showed dose-dependent activity. Future work will confirm the hits in vitro before studying whether Parkinson's-like phenotypes in the SNCA-OVX mice can be ameliorated or reversed by treatment with the compounds.
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Jang, Wai-chi, and 張慧芝. "Responses of retinal pigment epithelial cells to anoxic/hypoxic stressafter hypoxia-inducible factor-1-alpha down-regulation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43571980.
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Traini, Mathew Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Modelling aspects of neurodegeneration in Saccharomyces cerevisiae." Publisher:University of New South Wales. Biotechnology & Biomolecular Sciences, 2009. http://handle.unsw.edu.au/1959.4/43383.
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The neurodegenerative disorders Alzheimer??s Disease (AD) and Parkinson??s Disease (PD) are characterised by the accumulation of misfolded amyloid beta 1-42 peptide (Aβ1-42) or α-synuclein, respectively. In both cases, there is extensive evidence to support a central role for these aggregation-prone molecules in the progression of disease pathology. However, the precise mechanisms through which Aβ1-42 and α-synuclein contribute to neurodegeneration remain unclear. Organismal, cellular and in vitro models are under development to allow elucidation of these mechanisms. A cellular system for the study of intracellular Aβ1-42 misfolding and localisation was developed, based on expression of an Aβ1-42-GFP fusion protein in the model eukaryote Saccharomyces cerevisiae. This system relies on the known inverse relationship between GFP fluorescence, and the propensity to misfold of an N-terminal fusion domain. To discover cellular processes that may affect the misfolding and localisation of intracellular Aβ1-42, the Aβ1-42-GFP reporter was transformed into the S. cerevisiae genome deletion mutant collection and screened for fluorescence. 94 deletion mutants exhibited increased Aβ1-42-GFP fluorescence, indicative of altered Aβ1-42 misfolding. These mutants were involved in a number of cellular processes with suspected relationships to AD, including the tricarboxylic acid cycle, chromatin remodelling and phospholipid metabolism. Detailed examination of mutants involved in phosphatidylcholine synthesis revealed the potential for phospholipid composition to influence the intracellular aggregation and localisation of Aβ1-42. In addition, an existing S. cerevisiae model of α-synuclein pathobiology was extended to study the effects of compounds that have been hypothesized to be environmental risk factors leading to increased risk of developing PD. Exposure of cells to aluminium, dieldrin and compounds generating reactive oxygen species enhanced the toxicity of α- synuclein expression, supporting suggested roles for these agents in the onset and development of PD. Expression of α-synuclein-GFP in phosphatidylcholine synthesis mutants identified in the Aβ1-42-GFP fluorescence screen resulted in dramatic alteration of α-synuclein localisation, indicating a common involvement of phospholipid metabolism and composition in modulating the behaviours of these two aggregation-prone proteins.
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林勇行 and Yung-hang Lam. "Sonographic features of fetuses with homozygous [alpha]-thalassaemia-1during early pregnancy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31981744.
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Kawser, Choudhury Ali. "Regulation of secretion of #alpha#-2 macroglobulin by hepatic lipocytes in relation to hepatic fibrosis." Thesis, University of Southampton, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240644.
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Luth, Eric Sloan. "Physiological and Pathological Characterization of Alpha-Synuclein Oligomers." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11513.
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α-Synuclein (αSyn) is highly abundant cytosolic protein whose conversion into insoluble fibrils is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Despite decades of research, fundamental questions regarding αSyn biology are unresolved. Soluble, prefibrillar oligomers, not their fibrillar end products, are believed to be neurotoxic in humans and in disease models, but their mechanism of action remains unknown. Evidence from our lab and others increasingly suggests that, in healthy cells, αSyn does not exist purely as an unfolded monomer, as the field has long believed, but also as aggregation-resistant, α-helical oligomers; however, their physiological role remains controversial. Thus, my aim was twofold: to characterize toxic αSyn species in the context of mitochondrial dysfunction, a central phenotypic feature of PD; and to purify helical αSyn oligomers from human brain to enable further characterization of physiological αSyn.
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Clemons-miller, Annette R. "Tnf(alpha)-dependent and Tnf(alpha)-independent Activation of Macrophage Effector Function." Digital Commons @ East Tennessee State University, 1998. https://dc.etsu.edu/etd/2894.
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Tumor necrosis factor α (TNFα) is a pleiotropic cytokine that is predominantly produced by activated macrophages. The effects of TNFα are as diverse as the cells with which it interacts, e.g., stimulating fibroblast growth, exerting cytotoxic/cytostatic; activity against various human and murine cell lines, promoting inflammation through upregulation of endothelial adhesion molecules and IL-8 production. Yet TNFα is best known, and in fact was originally described, for its role in the bacterial-induced hemorrhagic necrosis of tumors and exacerbation of septic shock in which aberrant TNFα production leads to vascular collapse, cachexia, multiple organ failure, and ultimately death in as many as 100,000 people each year in the United States alone. LPS, a component of the outer cell wall of gram-negative bacteria, is the principal inducer of macrophage TNFα production. TNFα production can be enhanced by IFNγ which also induces upregulation of TNFα receptors allowing for the establishment of a TNFα autocrine loop. It has been hypothesized that autocrine TNFα stimulation plays a critical role in the induction of macrophage effector function, e.g., nitric oxide production. This dissertation represents efforts to evaluate the respective roles of the TNFα receptors in the induction of macrophage effector function, in addition to examining the mechanism by which autocrine TNFα exerts its effects on macrophages. Exploiting the species specificity of the murine TNFα receptor type 2 (TNF-R2), splenic macrophages were stimulated with human TNFα (which binds to TNF-R1 but not TNF-R2), in the presence of IFNγ. Human TNFα was effective in the induction of nitric oxide production, albeit at concentrations 12.5-fold greater than those required by murine TNFα to achieve the same result. Addition of anti-TNF-R1 completely inhibited the murine TNFα mediated induction of macrophage effector function. However, treatment with anti-TNF-R2 resulted in partial inhibition of macrophage activation. Taken together this data suggests that the primary TNFα mediated signals involved in macrophage activation are transduced through TNF-R1, although TNF-R2 appears to contribute to the intensity of the macrophage response. To evaluate the role of autocrine TNFα signaling in the induction of macrophage effector function, immortalized macrophages from normal C57Bl/6J mice (B6/J2) and C57Bl/6J mice containing gene targeted disruptions of the TNF-R1 and TNF-R2 genes (TRN) were stimulated under CD14-dependent and CD14-independent conditions. Although the B6/J2 and TRN clones mounted similar NO responses to LPS in the presence of serum, the TRN macrophages generated a weak nitric oxide response as compared to B6/J2 when stimulated with LPS under serum-free conditions. The involvement of TNFα autocrine stimulation in the CD14-independent activation was corroborated by the ability of soluble TNF-R1 to inhibit the response of B6/J2 macrophages to LPS in serum-free medium. CD14-independent LPS stimulation of TRN and B6/J2 resulted in equivalent levels of IL-1β, TNFα, and NOS gene expression, as determined by RT-PCR, and in release of equivalent amounts of biologically active TNFα. However, western blot analysis revealed that NOS protein production by TRN was as much as 50% less than that produced by B6/J2. These results indicate that autocrine TNFα stimulation contributes to the signaling pathways initiated by ligation of CD14-independent LPS receptors and may be involved in NOS post-transcriptional regulation.
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Cheung, Peter. "Activation of the endogenous alpha-globin gene in non-erythroid cells by herpes simplex virus." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0007/NQ42837.pdf.
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McAndrew, Joanne. "The role of alpha transforming growth factor in the control of the normal and malignant breast." Thesis, University of Liverpool, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333565.
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劉國培 and Kwok-pui Lau. "Clinicopathological roles of transforming growth factor alpha (TGFα) in papillary thyroid carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39558733.
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Chermenina, Maria. "GDNF and alpha-synuclein in nigrostriatal degeneration." Doctoral thesis, Umeå universitet, Histologi med cellbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-91811.
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Parkinson’s disease is a common neurological disorder with a complex etiology. The disease is characterized by a progressive loss of dopaminergic cells in the substantia nigra, which leads to motor function and sometimes cognitive function disabilities. One of the pathological hallmarks in Parkinson’s disease is the cytoplasmic inclusions called Lewy bodies found in the dopamine neurons. The aggregated protein α-synuclein is a main component of Lewy bodies. In view of severe symptoms and the upcoming of problematic side effects that are developed by the current most commonly used treatment in Parkinson’s disease, new treatment strategies need to be elucidated. One such strategy is replacing the lost dopamine neurons with new dopamine-rich tissue. To improve survival of the implanted neurons, neurotrophic factors have been used. Glial cell line-derived neurotrophic factor (GDNF), which was discovered in 1993, improves survival of ventral mesencephalic dopamine neurons and enhances dopamine nerve fiber formation according to several studies. Thus, GDNF can be used to improve dopamine-rich graft outgrowth into the host brain as well as inducing sprouting from endogenous remaining nerve fibers. This study was performed on Gdnf gene-deleted mice to investigate the role of GDNF on the nigrostriatal dopamine system. The transplantation technique was used to create a nigrostriatal microcircuit from ventral mesencephalon (VM) and the lateral ganglionic eminence (LGE) from different Gdnf gene-deleted mice. The tissue was grafted into the lateral ventricle of wildtype mice. The results revealed that reduced concentrations of GDNF, as a consequence from the Gdnf gene deletion, had effects on survival of dopamine neurons and the dopamine innervation of the nigrostriatal microcircuit. All transplants had survived at 3 months independently of Gdnf genotype, however, the grafts derived from Gdnf gene-deleted tissue had died at 6 months. Transplants with partial Gdnf gene deletion survived up to 12 months after transplantation. Moreover, the dopaminergic innervation of striatal co-grafts was impaired in Gdnf gene-deleted tissue. These results highlight the role of GDNF for long-term maintenance of the nigrostriatal dopamine system. To further investigate the role of GDNF expression on survival and organization of the nigrostriatal dopamine system, VM and LGE as single or combined to double co-grafts created from mismatches in Gdnf genotypes were transplanted into the lateral ventricle of wildtype mice. Survival of the single grafts was monitored over one year using a 9.4T MR scanner. The size of single LGE transplants was significantly reduced by the lack of GDNF already at 2 weeks postgrafting while the size of single VM was maintained over time, independently of GDNF expression. The double grafts were evaluated at 2 months, and the results revealed that lack of GDNF in LGE reduced the dopamine cell survival, while no loss of dopamine neurons was found in VM single grafts. The dopaminergic innervation of LGE was affected by absence of GDNF, which also caused a disorganization of the striatal portion of the co-grafts. Small, cytoplasmic inclusions were frequently found in the dopamine neurons in grafts lacking GDNF expression. These inclusions were not possible to classify as Lewy bodies by immunohistochemistry and the presence of phospho-α-synuclein and ubiquitin; however, mitochondrial dysfunction could not be excluded. To further study the death of the dopamine neurons by the deprivation of GDNF, the attention was turned to how Lewy bodies are developed. With respect to the high levels of α-synuclein that was found in the striatum, this area was selected as a target to inject the small molecule – FN075, which stimulates α-synuclein aggregation, to further investigate the role of α-synuclein in the formation of cytoplasmic inclusions. The results revealed that cytoplasmic inclusions, similar to those found in the grafts, was present at 1 month after the injection, while impairment in sensorimotor function was exhibited, the number of dopamine neurons was not changed at 6 months after the injection. Injecting the templator to the substantia nigra, however, significantly reduced the number of TH-positive neurons at 3 months after injection. In conclusion, these studies elucidate the role of GDNF for maintenance and survival of the nigrostriatal dopamine system and mechanisms of dopamine cell death using small molecules that template the α-synuclein aggregation.
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Akerman, Beverly. "Molecular studies of the alpha globin genes in Quebec populations." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66253.
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Morgan, Sophie. "The prion-like properties of assembled human alpha-synuclein." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277553.
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The pathological hallmark of many age-related neurodegenerative diseases is the presence of proteinaceous inclusions in nerve cells and glial cells. Alpha-synuclein is the main component of the inclusions of Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, as well as of rarer diseases, collectively called synucleinopathies. For a long time, it was widely believed that neurodegenerative diseases were cell-autonomous; however, a more recent hypothesis has suggested that some misfolded proteins resemble prions. Thus, aggregated alpha-synuclein shares features of PrPSc, the scrapie form of the prion protein. The aim of this thesis was to further characterize the prion-like properties of aggregated alpha-synuclein by studying the pathways of seeded aggregation, and to identify the species of alpha-synuclein responsible. I present evidence, using a HEK 293T cell model, that filamentous protein was the most seed-potent form of alpha-synuclein. Recombinant aggregated protein, aggregated alpha-synuclein from mice transgenic for A53T alpha-synuclein, as well as alpha-synuclein aggregates from Parkinson’s disease and multiple system atrophy brains, seeded aggregation. The mechanisms of alpha-synuclein internalization and intracellular trafficking, and how these processes affect seeded aggregation, are not fully understood. I showed that internalization of alpha-synuclein aggregates occurs through clathrin- and dynamin-independent, Cdc42-, actin- and PI3K-dependent endocytosis. Alpha-synuclein aggregates are trafficked to the endolysosomal pathway; a small fraction of lysosomes ruptures, which induces aggregation of expressed cytoplasmic alpha-synuclein, and disruption of autophagy, which in turn enhances seeded aggregation. These findings expand knowledge of the prion-like properties of assembled alpha-synuclein and identify novel mechanisms with therapeutic potential.