Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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Master Thesis Investigation of Autophagy Related Markers in Brain Tissue of Early-Onset Tay-Sachs Disease Mouse Models(Izmir Institute of Technology, 2018) Ateş, Nurselin; Ateş, Nurselin; Seyrantepe, Volkan; Seyrantepe, Volkan; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyTay-Sachs disease is an autosomal recessively inherited lysosomal storage disorder that mainly affects the central nervous system. It is caused by mutations on the HEXA gene encoding α-subunit of β-Hexosaminidase A enzyme. The enzyme normally catalyses GM2 to GM3 conversion but when it is absent or dysfunctional the GM2 degradation is interrupted. Progressive accumulation of the undegraded GM2 ganglioside in neurons causes neurodegeneration and eventual death for the patient. The Hexa-/- mice generated as Tay-Sachs model was nearly normal and a bypass mechanism mediated by a sialidase was discovered. Neu3 sialidase involvement in ganglioside degradation in the Tay-Sachs disease pathology was reported and the Hexa-/-Neu3-/- mice was observed to mimic the neuropathologic and clinical phenotype of the disease. Therefore, it can be used as early-onset-Tay-Sachs disease mouse model. Lysosomal storage diseases have been reported as disorders of autophagy as the lysosomal accumulation expected to affects the autophagical-lysosomal pathway in one way or another. In the concept of our study comparative analysis of WT, Hexa -/- ,Neu3 -/- and Hexa -/- Neu3 -/- mice provided the information that early-onset Tay-Sachs disease model exhibit impairment in autophagic flux and secondary accumulation of autophagic components. The effect of abnormal GM2 and this secondary accumulation on apoptotic regulators and trigger factors were also investigated. In the light of our study, impairment in autophagic flux, increased oxidative stress and ER-stress are involved in the disease pathology of early-onset Tay-Sachs disease mouse model.Master Thesis Brain Lipid Profiling of Triply Mouse Model With the Deficiencies of Sialidase Neu1, Neu4 and Ss-Hexosaminidase a Enzymes(Izmir Institute of Technology, 2011) Pekmezci, Zehra Kevser; Seyrantepe, Volkan; Seyrantepe, Volkan; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyTay-Sachs disease is a severe lysosomal storage disorder caused by mutations in the HEXA gene coding for α subunit of lysosomal β-hexosaminidase A enzyme, which converts GM2 to GM3 ganglioside. HexA-/- mice, depleted of β-hexosaminidase A enzyme, remain asymptomatic to 1 year of age, so it was thought there is a difference between human and mice lipid degradation. Previously identified a novel ganglioside metabolizing sialidase, Neu4, is abundantly expressed in mouse brain neurons. It was demonstrated that mice with targeted disruption of both HexA and Neu4 genes (HexA-/- Neu4-/-) show accumulating GM2 ganglioside and epileptic seizures with 40% penetrance. Since all mice didn't show symptoms, it was suggested that Neu4 is not the only sialidase contributing to the metabolic bypass in HexA-/- mice (Seyrantepe et al. 2010). Therefore, we studied the role of another sialidase Neu 1 in glycolipid degradation. We profiled brain glycolipid content of triple deficient mouse model with the deficiency of β-hexosaminidase A (0% activity), sialidase Neu4 (0% activity) and sialidase Neu 1 (10% activity) (NeoIn) by thin layer chromatography. Analysis of both double (HexA-/-NeoIn-/-) and triple (HexA-/-Neu4-/-NeoIn-/-) mice models showed that sialidase Neu 1 deficency causes not significant difference in brain lipid profile and though also other sialidase/sialidases might have role in glycolipid degradation pathway in mice.