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

2020 ◽  
Author(s):  
Secil Akyildiz Demir ◽  
Zehra Kevser Timur ◽  
Nurselin Ates ◽  
Luis Alarcon Martinez ◽  
Volkan Seyrantepe
Keyword(s):  
Mouse Model ◽  
Early Onset ◽  
Premature Death ◽  
Lysosomal Storage ◽  
Gm2 Gangliosidosis ◽  
Astrocyte Activation ◽  
Peripheral Blood Mononuclear ◽  
Gm2 Ganglioside ◽  
Tay Sachs Disease ◽  
Progressive Accumulation

Abstract BackgroundTay-Sachs disease (TSD), a type of GM2-gangliosidosis, is a progressive neurodegenerative lysosomal storage disorder, caused by mutations in the a subunit of lysosomal β-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 genotype Hexa-/-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 in Hexa-/-Neu3-/- mice relevant to neuroinflammation is poorly understood. MethodWe investigated the onset and progression of neuropathological and neuroinflammatory changes in the cortex, cerebellum and retina of Hexa-/-Neu3-/- mice and littermate wild-type as well as Hexa-/- and Neu3-/- mice by using a combination of expression, immunofluorescence and behavioral analyses. ResultsWe found elevated levels of pro-inflamatory pro-inflammatory cytokine and chemokine transcripts, such as Ccl2, Ccl3, Ccl4 and Cxcl10 and also extensive microglial and astrocyte activation and proliferation accompanied by in peripheral blood mononuclear cell infiltration in neurons and oligodendrocytes. Behavioral tests demonstrated high level of anxiety, and age dependent loss in both memory and muscle strength in Hexa-/-Neu3-/- mice compared with that in the controls. ConclusionAltogether, our data suggest that Hexa-/-Neu3-/- mice display a phenotype similar to human TSD patients suffering from chronic neuroinflammation triggered by GM2 accumulation. Our observations collectively suggest a hypothesis that modulation of Ccl2, Ccl3, Ccl4 and Cxcl10 or of their receptors, in combination with traditional drugs such as propagermanium, may provide a novel approach for the management of disease and better understanding of the neuropathology in a mouse model of early-onset Tay-Sachs disease.

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

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Seçil Akyıldız Demir ◽  
Zehra Kevser Timur ◽  
Nurselin Ateş ◽  
Luis Alarcón Martínez ◽  
Volkan Seyrantepe
Keyword(s):  
Mouse Model ◽  
Early Onset ◽  
Premature Death ◽  
Lysosomal Storage ◽  
Gm2 Gangliosidosis ◽  
Astrocyte Activation ◽  
Peripheral Blood Mononuclear ◽  
Gm2 Ganglioside ◽  
Tay Sachs Disease ◽  
Progressive Accumulation

Abstract Background Tay-Sachs disease (TSD), a type of GM2-gangliosidosis, is a progressive neurodegenerative lysosomal storage disorder caused by mutations in the α subunit of the lysosomal β-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 genotype Hexa−/−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 in Hexa−/−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 of Hexa−/−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 in Hexa−/−Neu3−/− mice compared with that in the controls. Conclusion Altogether, our data suggest that Hexa−/−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.

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

2020 ◽  
Author(s):  
Secil Akyildiz Demir ◽  
Zehra Kevser Timur ◽  
Nurselin Ates ◽  
Luis Alarcon Martinez ◽  
Volkan Seyrantepe
Keyword(s):  
Mouse Model ◽  
Early Onset ◽  
Premature Death ◽  
Lysosomal Storage ◽  
Gm2 Gangliosidosis ◽  
Astrocyte Activation ◽  
Peripheral Blood Mononuclear ◽  
Gm2 Ganglioside ◽  
Tay Sachs Disease ◽  
Progressive Accumulation

Abstract Background Tay-Sachs disease (TSD), a type of GM2-gangliosidosis, is a progressive neurodegenerative lysosomal storage disorder; caused by mutations in the a subunit of the lysosomal β-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 genotype Hexa -/- 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 in Hexa -/- 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 of Hexa -/- 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 neurons and oligodendrocytes. Behavioral tests demonstrated a high level of anxiety, and age-dependent loss in both spatial learning and fear memory in Hexa -/- Neu3 -/- mice compared with that in the controls. Conclusion Altogether, our data suggest that Hexa -/- 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.

scholarly journals Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

2020 ◽  
Vol 9 (4) ◽  
pp. 1050 ◽  
Author(s):  
Ecem Kaya ◽  
David A. Smith ◽  
Claire Smith ◽  
Barry Boland ◽  
Michael Strupp ◽  
...  
Keyword(s):  
Mouse Model ◽  
Sandhoff Disease ◽  
Lysosomal Storage ◽  
Gm2 Ganglioside ◽  
Beneficial Effects ◽  
New Therapeutic Approaches ◽  
Late Endosomes ◽  
Altered Glucose ◽  
Cerebellar Ataxias ◽  
Niemann Pick

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

Alteration in redox homeostasis in early-onset Tay-Sachs disease mouse model

2020 ◽  
Vol 129 (2) ◽  
pp. S147
Author(s):  
Volkan Seyrantepe ◽  
Nurselin Ates ◽  
Hatice Hande Basırlı ◽  
Secil Akyildiz Demir ◽  
Berkay Dagalp ◽  
...  
Keyword(s):  
Mouse Model ◽  
Early Onset ◽  
Redox Homeostasis ◽  
Tay Sachs Disease

scholarly journals Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

2019 ◽  
Vol 28 (23) ◽  
pp. 3867-3879 ◽  
Author(s):  
Sophia-Martha kleine Holthaus ◽  
Saul Herranz-Martin ◽  
Giulia Massaro ◽  
Mikel Aristorena ◽  
Justin Hoke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Motor Coordination ◽  
Transmembrane Protein ◽  
Batten Disease ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Enzyme Replacement

Abstract The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

Abnormal GM2 accumulation alters the function of the autophagic pathway in early-onset Tay-Sachs disease mouse model

2018 ◽  
Vol 123 (2) ◽  
pp. S129-S130
Author(s):  
Volkan Seyrantepe ◽  
Nurselin Ates ◽  
Melike Can ◽  
Tugce Sengul ◽  
Secil Akyildiz Demir
Keyword(s):  
Mouse Model ◽  
Early Onset ◽  
Tay Sachs Disease

scholarly journals Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease

2018 ◽  
Vol 96 (12) ◽  
pp. 1359-1373 ◽  
Author(s):  
Yuehong Chen ◽  
Jinlong Jian ◽  
Aubryanna Hettinghouse ◽  
Xueheng Zhao ◽  
Kenneth D. R. Setchell ◽  
...  
Keyword(s):  
Lysosomal Storage ◽  
Gm2 Ganglioside ◽  
Tay Sachs Disease ◽  
Hexosaminidase A

scholarly journals Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

2019 ◽  
Author(s):  
Sophia-Martha kleine Holthaus ◽  
Saul Martin-Herranz ◽  
Giulia Massaro ◽  
Mikel Aristorena ◽  
Justin Hoke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Motor Coordination ◽  
Transmembrane Protein ◽  
Batten Disease ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Enzyme Replacement

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and preclinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

scholarly journals Characterization and phosphoproteomic analysis of a human immortalized podocyte model of Fabry disease generated using CRISPR/Cas9 technology

2016 ◽  
Vol 311 (5) ◽  
pp. F1015-F1024 ◽  
Author(s):  
Ester M. Pereira ◽  
Anatália Labilloy ◽  
Megan L. Eshbach ◽  
Ankita Roy ◽  
Arohan R. Subramanya ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Human Kidney ◽  
Premature Death ◽  
Antibody Array ◽  
Cell Models ◽  
Lysosomal Storage ◽  
Protein Levels ◽  
Gla Gene ◽  
Fabry Nephropathy ◽  
And Control

Fabry nephropathy is a major cause of morbidity and premature death in patients with Fabry disease (FD), a rare X-linked lysosomal storage disorder. Gb3, the main substrate of α-galactosidase A (α-Gal A), progressively accumulates within cells in a variety of tissues. Establishment of cell models has been useful as a tool for testing hypotheses of disease pathogenesis. We applied CRISPR/Cas9 genome editing technology to the GLA gene to develop human kidney cell models of FD in human immortalized podocytes, which are the main affected renal cell type. Our podocytes lack detectable α-Gal A activity and have increased levels of Gb3. To explore different pathways that could have distinct patterns of activation under conditions of α-gal A deficiency, we used a high-throughput antibody array to perform phosphorylation profiling of CRISPR/Cas9-edited and control podocytes. Changes in both total protein levels and in phosphorylation status per site were observed. Analysis of our candidate proteins suggests that multiple signaling pathways are impaired in FD.

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