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dc.contributor.authorDemir, Secil Akyildiz
dc.contributor.authorTimur, Zehra Kevser
dc.contributor.authorAtes, Nurselin
dc.contributor.authorMartinez, Luis Alarcon
dc.contributor.authorSeyrantepe, Volkan
dc.descriptionPubMed: 32951593en_US
dc.description.abstractBackground 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.en_US
dc.description.sponsorshipEMBO 2010 Installation Granten_US
dc.description.sponsorshipThis study was partially supported by EMBO 2010 Installation Grant to Prof Dr. Volkan Seyrantepe.en_US
dc.subjectTay-Sachs diseaseen_US
dc.subjectMouse modelen_US
dc.titleGM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs diseaseen_US
dc.relation.journalJournal of Neuroinflammationen_US
dc.contributor.departmentIzmir Isntitute of Technologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US

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