Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 4Citation - Scopus: 4Autophagic Flux Is Impaired in the Brain Tissue of Tay-Sachs Disease Mouse Model(Public Library of Science, 2023) Şengül, Tuğçe; Can, Melike; Ateş, Nurselin; Seyrantepe, VolkanTay-Sachs disease is a lethal lysosomal storage disorder caused by mutations in the HexA gene encoding the α subunit of the lysosomal β-hexosaminidase enzyme (HEXA). Abnormal GM2 ganglioside accumulation causes progressive deterioration in the central nervous system in Tay-Sachs patients. Hexa-/-mouse model failed to display abnormal phenotype. Recently, our group generated Hexa-/-Neu3-/-mouse showed severe neuropathological indications similar to Tay-Sachs patients. Despite excessive GM2 ganglioside accumulation in the brain and visceral organs, the regulation of autophagy has not been clarified yet in the Tay-Sachs disease mouse model. Therefore, we investigated distinct steps of autophagic flux using markers including LC3 and p62 in four different brain regions from the Hexa-/-Neu3-/-mice model of Tay-Sachs disease. Our data revealed accumulated autophagosomes and autophagolysosomes indicating impairment in autophagic flux in the brain. We suggest that autophagy might be a new therapeutic target for the treatment of devastating Tay-Sachs disease. © 2023 Sengul et al.Article Citation - WoS: 6Citation - Scopus: 6Analysis of Brain Lipids in the Early-Onset Tay–sachs Disease Mouse Model With the Combined Deficiency of Β-Hexosaminidase a and Neuraminidase 3(Frontiers Media S.A., 2022) Can, Melike; Şengül, Tuğçe; Akyıldız Demir, Seçil; İnci, Orhan K.; Basırlı, Hatice Hande; Seyrantepe, VolkanTay–Sachs disease is an autosomal recessively inherited lysosomal storage disease that results from loss-of-function mutations in the HEXA gene coding βhexosaminidase A. HEXA gene deficiency affects the central nervous system owing to GM2 ganglioside accumulation in lysosomes resulting in progressive neurodegeneration in patients. We recently generated a novel mice model with a combined deficiency of βhexosaminidase A and neuraminidase 3 (Hexa−/−Neu3−/−) that mimics both the neuropathological and clinical abnormalities of early-onset Tay–Sachs disease. Here, we aimed to explore the secondary accumulation of lipids in the brain of Hexa−/ −Neu3−/− mice.Conference Object Brain Lipid Profile of Early Onset Tay-Sachs Disease Mouse Model(Springernature, 2020) Şengül, Tuğçe; Can, Melike; Akyıldız Demir, Seçil; Klose, C.; Surma, M.; Seyrantepe, Volkan[Abstract Not Available]Conference Object Role of Oxidative Stress in the Pathogenesis of Tay-Sachs Disease Mouse Model(Springernature, 2020) Ateş, Nurselin; Başırlı, Hatice Hande; Çalışkan, Tufan Utku; Nalbant, Ayten; Seyrantepe, Volkan[Abstract Not Available]Article Citation - WoS: 37Citation - Scopus: 40Gm2 Ganglioside Accumulation Causes Neuroinflammation and Behavioral Alterations in a Mouse Model of Early Onset Tay-Sachs Disease(BioMed Central Ltd., 2020) Akyıldız Demir, Seçil; Timur, Zehra Kevser; Ateş, Nurselin; Martinez, Luis Alarcon; Seyrantepe, VolkanBackground Tay-Sachs disease (TSD), a type of GM2-gangliosidosis, is a progressive neurodegenerative lysosomal storage disorder caused by mutations in the alpha subunit of the lysosomal beta-hexosaminidase enzyme. This disease is characterized by excessive accumulation of GM2 ganglioside, predominantly in the central nervous system. Although Tay-Sachs patients appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to death. Recently, an early onset Tay-Sachs disease mouse model, with genotypeHexa-/-Neu3-/-, was generated. Progressive accumulation of GM2 led to premature death of the double KO mice. Importantly, this double-deficient mouse model displays typical features of Tay-Sachs patients, such as cytoplasmic vacuolization of nerve cells, deterioration of Purkinje cells, neuronal death, deceleration in movement, ataxia, and tremors. GM2-gangliosidosis is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage, and astrocyte activation, along with the production of inflammatory mediators. However, the mechanism of disease progression inHexa-/-Neu3-/-mice, relevant to neuroinflammation is poorly understood. Method In this study, we investigated the onset and progression of neuroinflammatory changes in the cortex, cerebellum, and retina ofHexa-/-Neu3-/-mice and control littermates by using a combination of molecular genetics and immunochemical procedures. Results We found elevated levels of pro-inflammatory cytokine and chemokine transcripts, such as Ccl2, Ccl3, Ccl4, and Cxcl10 and also extensive microglial and astrocyte activation and proliferation, accompanied by peripheral blood mononuclear cell infiltration in the vicinity of neurons and oligodendrocytes. Behavioral tests demonstrated a high level of anxiety, and age-dependent loss in both spatial learning and fear memory inHexa-/-Neu3-/-mice compared with that in the controls. Conclusion Altogether, our data suggest thatHexa-/-Neu3-/-mice display a phenotype similar to Tay-Sachs patients suffering from chronic neuroinflammation triggered by GM2 accumulation. Furthermore, our work contributes to better understanding of the neuropathology in a mouse model of early onset Tay-Sachs disease.Conference Object Abnormal Gm2 Accumulation Alters the Function of the Autophagic Pathway in Early-Onset Tay-Sachs Disease Mouse Model(Academic Press, 2018) Seyrantepe, Volkan; Ateş, Nurselin; Can, Melike; Şengül, Tuğçe; Akyıldız Demir, SeçilTay-Sachs disease (TSD) is an inborn error of metabolism, a prototypical lysosomal disease of the nervous system. In humans, the fatal infantile acute form is the most common, and with no current treatment, prevention and palliative care the only options. TSD mice did not mimic human infantile TSD, and although mice showed some early pathology and storage of GM2 ganglioside, clinical disease would take many months to develop. The extremely mild disease in the TSD mice was likely due to a biochemical bypass, a neuraminidase. We recently demostrated that at least one of the principal murine neuraminidase, Neu3, responsible for the biochemical bypass in the catabolism of the GM2 ganglioside.Article Citation - WoS: 54Citation - Scopus: 58Murine Sialidase Neu3 Facilitates Gm2 Degradation and Bypass in Mouse Model of Tay-Sachs Disease(Elsevier, 2018) Seyrantepe, Volkan; Akyıldız Demir, Seçil; Timur, Zehra Kevser; Von Gerichten, Johanna; Marsching, Christian; Erdemli, Esra; Öztaş, Emin; Takahashi, Kohta; Yamaguchi, Kazunori; Ateş, Nurselin; Dönmez Demir, Buket; Dalkara, Turgay; Erich, Katrin; Hopf, Carsten; Sandhoff, Roger; Miyagi, TaekoTay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the α subunit of lysosomal β-hexosaminidase A (HEXA), which converts GM2 to GM3 ganglioside. Unexpectedly, Hexa−/− mice have a normal lifespan and show no obvious neurological impairment until at least one year of age. These mice catabolize stored GM2 ganglioside using sialidase(s) to remove sialic acid and form the glycolipid GA2, which is further processed by β-hexosaminidase B. Therefore, the presence of the sialidase (s) allows the consequences of the Hexa defect to be bypassed. To determine if the sialidase NEU3 contributes to GM2 ganglioside degradation, we generated a mouse model with combined deficiencies of HEXA and NEU3. The Hexa−/− Neu3−/− mice were healthy at birth, but died at 1.5 to 4.5 months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of Hexa−/− Neu3−/− mice revealed the abnormal accumulation of GM2 ganglioside. Histological and immunohistochemical analysis demonstrated cytoplasmic vacuolation in the neurons. Electron microscopic examination of the brain, kidneys and testes revealed pleomorphic inclusions of many small vesicles and complex lamellar structures. The Hexa−/− Neu3−/− mice exhibited progressive neurodegeneration with neuronal loss, Purkinje cell depletion, and astrogliosis. Slow movement, ataxia, and tremors were the prominent neurological abnormalities observed in these mice. Furthermore, radiographs revealed abnormalities in the skeletal bones of the Hexa−/− Neu3−/− mice. Thus, the Hexa−/− Neu3−/− mice mimic the neuropathological and clinical abnormalities of the classical early-onset Tay-Sachs patients, and provide a suitable model for the future pre-clinical testing of potential treatments for this condition.