Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Review Citation - WoS: 6Citation - Scopus: 8Molecular Trojan Horses for Treating Lysosomal Storage Diseases(Academic Press, 2023) Leal, Andres Felipe; Rintz, Estera; Çelik, Betül; Ago, Yasuhiko; León, Daniel; İnci, Orhan Kerim; Seyrantepe, VolkanLysosomal storage diseases (LSDs) are caused by monogenic mutations in genes encoding for proteins related to the lysosomal function. Lysosome plays critical roles in molecule degradation and cell signaling through interplay with many other cell organelles, such as mitochondria, endoplasmic reticulum, and peroxisomes. Even though several strategies (i.e., protein replacement and gene therapy) have been attempted for LSDs with promising results, there are still some challenges when hard-to-treat tissues such as bone (i.e., cartilages, ligaments, meniscus, etc.), the central nervous system (mostly neurons), and the eye (i.e., cornea, retina) are affected. Consistently, searching for novel strategies to reach those tissues remains a priority. Molecular Trojan Horses have been well-recognized as a potential alternative in several pathological scenarios for drug delivery, including LSDs. Even though molecular Trojan Horses refer to genetically engineered proteins to overcome the blood-brain barrier, such strategy can be extended to strategies able to transport and deliver drugs to specific tissues or cells using cell-penetrating peptides, monoclonal antibodies, vesicles, extracellular vesicles, and patient-derived cells. Only some of those platforms have been attempted in LSDs. In this paper, we review the most recent efforts to develop molecular Trojan Horses and discuss how this strategy could be implemented to enhance the current efficacy of strategies such as protein replacement and gene therapy in the context of LSDs. © 2023Conference Object Elimination of the B4galnt1 Gene Normalizes Lifespan and Prevents Pathology in Tay-Sachs Disease Mice(Elsevier, 2023) Seyrantepe, VolkanTay-Sachs disease is a neurodegenerative lysosomal storage disorder caused by mutations in the Hexa gene, which encodes the alpha subunit of lysosomal ß-hexaminidase A (HEXA). HEXA is responsible for the conversion of GM2 to GM3, therefore the deficiency leads to the accumulation of GM2 in the lysosomes, neurodegeneration, and eventual death. Currently, there is no efficient therapy for the disease yet.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: 5Citation - Scopus: 5Sialidase Neu4 Deficiency Is Associated With Neuroinflammation in Mice(Springer, 2021) Timur, Zehra Kevser; İnci, Orhan Kerim; Akyıldız Demir, Seçil; Seyrantepe, VolkanSialidases catalyze the removal of sialic acid residues from glycoproteins, oligosaccharides, and sialylated glycolipids. Sialidase Neu4 is in the lysosome and has broad substrate specificity. Previously generated Neu4-/- mice were viable, fertile and lacked gross morphological abnormalities, but displayed a marked vacuolization and lysosomal storage in lung and spleen cells. In addition, we showed that there is an increased level of GD1a ganglioside and a markedly decreased level of GM1 ganglioside in the brain of Neu4-/- mice. In this study, we further explored whether sialidase Neu4 deficiency causes neuroinflammation. We demostrated that elevated level of GD1a and GT1b is associated with an increased level of LAMP1-positive lysosomal vesicles and Tunel-positive neurons correlated with alterations in the expression of cytokines and chemokines in adult Neu4-/- mice. Astrogliosis and microgliosis were also significantly enhanced in the hippocampus, and cerebellum. These changes in brain immunity were accompanied by motor impairment in these mice. Our results indicate that sialidase Neu4 is a novel mediator of an inflammatory response in the mouse brain due to the altered catabolism of gangliosides.Article Citation - WoS: 2Citation - Scopus: 2Identification of Cytoplasmic Sialidase Neu2-Associated Proteins by Lc-ms/Ms(Türk Biyokimya Derneği, 2019) Akyıldız Demir, Seçil; Seyrantepe, VolkanBackground: Cytoplasmic sialidase (NEU2) plays an active role in removing sialic acids from oligosaccharides, gly-copeptides, and gangliosides in mammalian cells. NEU2 is involved in various cellular events, including cancer metabolism, neuronal and myoblast differentiation, proliferation, and hypertrophy. However, NEU2-interacting protein(s) within the cell have not been identified yet. Objective: The aim of this study is to investigate NEU2 interacting proteins using two-step affinity purification (TAP) strategy combined with mass spectrometry analysis. Methods: In this study, NEU2 gene was cloned into the pCTAP expression vector and transiently transfected to COS-7 cells by using PEI. The most efficient expression time of NEU2- tag protein was determined by real-time PCR and Western blot analysis. NEU2-interacting protein(s) were investigated by using TAP strategy combined with two different mass spectrometry experiment; LC-MS/MS and MALDI TOF/TOF. Results: Here, mass spectrometry analysis showed four proteins; a-actin, beta-actin, calmodulin and histone H1.2 proteins are associated with NEU2. The interactions between NEU2 and actin filaments were verified by Western blot analysis and immunofluorescence analysis. Conclusions: Our study suggests that association of NEU2 with actin filaments and other protein(s) could be important for understanding the biological role of NEU2 in mammalian cells.