GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease

Demir, Secil Akyildiz; Timur, Zehra Kevser; Ateş, Nurselin; Martínez, Luis A Díaz; Seyrantepe, Volkan

doi:10.1186/s12974-020-01947-6

Cited by 33 publications

(15 citation statements)

References 57 publications

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“…6), including UDP-glucose ceramide glucosyltransferase (UGCG ), the enzyme converting ceramide to glucosylceramide, as well as β-galactosidase (GLB1), neuraminidase 1 (NEU1), and hexosaminidase α (HEXA), which convert gangliosides back to glucosylceramide. In addition to reduced concentrations of HexCer, the downregulation of these enzymes could theoretically lead to an accumulation of ceramides and GM1, -2, and -3 gangliosides, all of which have been identified as contributors of insulin resistance in various cell types (Demir et al 2020;Haynes et al 2012;Kajihara et al 2020;Lipina and Hundal, 2015;Sasaki et al 2018;Wang et al 2014;Yamashita et al 2003). However, ceramide concentrations were not significantly increased, possibly due to the observed downregulation of ceramide synthases.…”

Section: Discussionmentioning

confidence: 98%

Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes

Ahonen

Höring

Nguyen³

et al. 2022

Mol Med

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Background Thyroid hormone responsive protein (THRSP) is a lipogenic nuclear protein that is highly expressed in murine adipose tissue, but its role in humans remains unknown. Methods We characterized the insulin regulation of THRSP in vivo in human adipose tissue biopsies and in vitro in Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. To this end, we measured whole-body insulin sensitivity using the euglycemic insulin clamp technique in 36 subjects [age 40 ± 9 years, body mass index (BMI) 27.3 ± 5.0 kg/m2]. Adipose tissue biopsies were obtained at baseline and after 180 and 360 min of euglycemic hyperinsulinemia for measurement of THRSP mRNA concentrations. To identify functions affected by THRSP, we performed a transcriptomic analysis of THRSP-silenced SGBS adipocytes. Mitochondrial function was assessed by measuring mitochondrial respiration as well as oxidation and uptake of radiolabeled oleate and glucose. Lipid composition in THRSP silencing was studied by lipidomic analysis. Results We found insulin to increase THRSP mRNA expression 5- and 8-fold after 180 and 360 min of in vivo euglycemic hyperinsulinemia. This induction was impaired in insulin-resistant subjects, and THRSP expression was closely correlated with whole-body insulin sensitivity. In vitro, insulin increased both THRSP mRNA and protein concentrations in SGBS adipocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. A transcriptomic analysis of THRSP-silenced adipocytes showed alterations in mitochondrial functions and pathways of lipid metabolism, which were corroborated by significantly impaired mitochondrial respiration and fatty acid oxidation. A lipidomic analysis revealed decreased hexosylceramide concentrations, supported by the transcript concentrations of enzymes regulating sphingolipid metabolism. Conclusions THRSP is regulated by insulin both in vivo in human adipose tissue and in vitro in adipocytes, and its expression is downregulated by insulin resistance. As THRSP silencing decreases mitochondrial respiration and fatty acid oxidation, its downregulation in human adipose tissue could contribute to mitochondrial dysfunction. Furthermore, disturbed sphingolipid metabolism could add to metabolic dysfunction in obese adipose tissue.

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Section: Discussionmentioning

confidence: 98%

Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes

Ahonen

Höring

Nguyen³

et al. 2022

Mol Med

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“…NEU2 and NEU4 were shown to inhibit cancers 43 , 44 . NEU3 was reported to act as a pro-inflammatory mediator in the intestine and lung, but trigger inflammation in brain 45 – 47 . Besides NEU1 that has been decoded in this work, the roles of NEU2, NEU3, and NEU4 in CKD progression need to be explored in-depth in the near future.…”

Section: Discussionmentioning

confidence: 99%

Neuraminidase 1 promotes renal fibrosis development in male mice

Chen

Liu²,

Shi³

et al. 2023

Nat Commun

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The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the role of neuraminidase 1 (NEU1) in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models. We find that NEU1 is significantly upregulated in the fibrotic kidneys of patients and mice. Functionally, tubular epithelial cell-specific NEU1 knockout inhibits epithelial-to-mesenchymal transition, inflammatory cytokines production, and collagen deposition in mice. Conversely, NEU1 overexpression exacerbates progressive renal fibrosis. Mechanistically, NEU1 interacts with TGFβ type I receptor ALK5 at the 160-200aa region and stabilizes ALK5 leading to SMAD2/3 activation. Salvianolic acid B, a component of Salvia miltiorrhiza, is found to strongly bind to NEU1 and effectively protect mice from renal fibrosis in a NEU1-dependent manner. Collectively, this study characterizes a promotor role for NEU1 in renal fibrosis and suggests a potential avenue of targeting NEU1 to treat kidney diseases.

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“…The myelin sheath in the central nervous system is specifically formed in oligodendrocytes. In the previous study, we demonstrated that abnormal GM2 accumulation in the brain of Hexa−/−Neu3−/− mouse also causes the death of myelin-forming cells ( Demir et al, 2020 ). Here, our shotgun lipidomics data showed a significant decrease in the level of SMs in both the cortex and hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Brain Lipids in the Early-Onset Tay–Sachs Disease Mouse Model With the Combined Deficiency of β-Hexosaminidase A and Neuraminidase 3

Can

Şengül

Demir

et al. 2022

Front. Mol. Biosci.

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Introduction: Tay–Sachs disease is an autosomal recessively inherited lysosomal storage disease that results from loss-of-function mutations in the HEXA gene coding β-hexosaminidase 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 β-hexosaminidase 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.Materials and Methods: In the cortex and hippocampus of five-month-old WT, Hexa−/−, Neu3−/−, and Hexa−/−Neu3−/− mice, lipid levels belonging to glycerolipids, glycerophospholipids, and sterol lipids were evaluated using a shotgun lipidomics approach. The levels of myelin were also assessed by luxol fast blue staining and immunohistochemistry using antibodies against myelin basic protein. We further examined glycoconjugate and cholesterol levels by periodic acid–Schiff and filipin staining, respectively. Toluidine blue staining was also performed to display axonal degeneration.Results: Among glycerophospholipids, we demonstrated elevated levels of phosphatidylcholine-ether and lysophosphatidylcholine while decreased levels of phosphatidylcholine and phosphatidylserine in both cortex and hippocampus of Hexa−/−Neu3−/− mice. In the glycerolipid class, we showed an alleviated level of sphingomyelin in both cortex and hippocampus, but the higher levels of diacylglycerol and triacylglycerol were detected in only the hippocampus of Hexa−/−Neu3−/− mice. The lower level of sterol was also detected in the cortex of Hexa−/−Neu3−/− mice but not in the hippocampus.Histochemical studies showed a decrease in the myelin level and axonal degeneration indicating neuronal pathology in the brain of Hexa−/−Neu3−/− mice. Although glycoconjugate accumulation was evident both in the cortex and hippocampus, we did not detect any changes in the level of cholesterol.Conclusion: Our results indicate that alterations in lipid metabolism and neuropathology, such as demyelination and axonal degeneration, might be related to the dysfunctionality of lipid-related cellular pathways like autophagy. Understanding of brain-specific lipid alterations contributes to evaluating the effectiveness of treatments in Hexa−/−Neu3−/− mice in future studies.

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GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early onset Tay-Sachs disease

Cited by 33 publications

References 57 publications

Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes

Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes

Neuraminidase 1 promotes renal fibrosis development in male mice

Analysis of Brain Lipids in the Early-Onset Tay–Sachs Disease Mouse Model With the Combined Deficiency of β-Hexosaminidase A and Neuraminidase 3

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