Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides
Sialylated glycolipids, gangliosides play an essential role in the central nervous system regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in development of severe neurological disorders, gangliosidoses manifesting with neurodegene...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
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Federation of American Society of Experimental Biology (FASEB)
2017
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| _version_ | 1826271825551687680 |
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| author | Pan, X De Britto Pará De Aragão, C Velasco-Martin, J Priestman, D Wu, H Takahashi, K Yamaguchi, K Sturiale, L Garozzo, D Platt, F Lamarche-Vane, N Morales, C Miyagi, T Pshezhetsky, A |
| author_facet | Pan, X De Britto Pará De Aragão, C Velasco-Martin, J Priestman, D Wu, H Takahashi, K Yamaguchi, K Sturiale, L Garozzo, D Platt, F Lamarche-Vane, N Morales, C Miyagi, T Pshezhetsky, A |
| author_sort | Pan, X |
| collection | OXFORD |
| description | Sialylated glycolipids, gangliosides play an essential role in the central nervous system regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in development of severe neurological disorders, gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that two mammalian enzymes, neuraminidases 3 and 4 play important role in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In the neuraminidase 3-4 double knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies and memory loss whereas their cortical and hippocampal neurons have lower rate of neuritogenesis in vitro. Double knockout mice also have reduced levels of GM1 ganglioside and myelin in neuronal axons. Besides, neuraminidase 3 deficiency drastically increased storage of GM2 in the brain tissues of the asymptomatic mouse model of the severe human gangliosidosis, Tay-Sachs disease indicating that this enzyme is responsible for the metabolic bypass of the β-hexosaminidase A deficiency. Together, our results provide the first in vivo evidence that neuraminidases 3 and 4 have important roles in CNS function by catabolizing gangliosides and preventing their storage in lipofuscin bodies. |
| first_indexed | 2024-03-06T22:02:50Z |
| format | Journal article |
| id | oxford-uuid:4f2d2ff0-de7b-4371-8aed-703edcb40d0e |
| institution | University of Oxford |
| last_indexed | 2024-03-06T22:02:50Z |
| publishDate | 2017 |
| publisher | Federation of American Society of Experimental Biology (FASEB) |
| record_format | dspace |
| spelling | oxford-uuid:4f2d2ff0-de7b-4371-8aed-703edcb40d0e2022-03-26T16:05:36ZNeuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosidesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4f2d2ff0-de7b-4371-8aed-703edcb40d0eSymplectic Elements at OxfordFederation of American Society of Experimental Biology (FASEB)2017Pan, XDe Britto Pará De Aragão, CVelasco-Martin, JPriestman, DWu, HTakahashi, KYamaguchi, KSturiale, LGarozzo, DPlatt, FLamarche-Vane, NMorales, CMiyagi, TPshezhetsky, ASialylated glycolipids, gangliosides play an essential role in the central nervous system regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in development of severe neurological disorders, gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that two mammalian enzymes, neuraminidases 3 and 4 play important role in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In the neuraminidase 3-4 double knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies and memory loss whereas their cortical and hippocampal neurons have lower rate of neuritogenesis in vitro. Double knockout mice also have reduced levels of GM1 ganglioside and myelin in neuronal axons. Besides, neuraminidase 3 deficiency drastically increased storage of GM2 in the brain tissues of the asymptomatic mouse model of the severe human gangliosidosis, Tay-Sachs disease indicating that this enzyme is responsible for the metabolic bypass of the β-hexosaminidase A deficiency. Together, our results provide the first in vivo evidence that neuraminidases 3 and 4 have important roles in CNS function by catabolizing gangliosides and preventing their storage in lipofuscin bodies. |
| spellingShingle | Pan, X De Britto Pará De Aragão, C Velasco-Martin, J Priestman, D Wu, H Takahashi, K Yamaguchi, K Sturiale, L Garozzo, D Platt, F Lamarche-Vane, N Morales, C Miyagi, T Pshezhetsky, A Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides |
| title | Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides |
| title_full | Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides |
| title_fullStr | Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides |
| title_full_unstemmed | Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides |
| title_short | Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides |
| title_sort | neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides |
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