Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction.
Glycosphingolipids (GSL) are important bioactive membrane components. GSLs containing sialic acids, known as gangliosides, are highly abundant in the brain and diseases of ganglioside metabolism cause severe early-onset neurodegeneration. The ganglioside GM2 is processed by β-hexosaminidase A and wh...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3003265 |
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| author | Alex S Nicholson David A Priestman Robin Antrobus James C Williamson Reuben Bush Shannon J McKie Henry G Barrow Emily Smith Kostantin Dobrenis Nicholas A Bright Frances M Platt Janet E Deane |
| author_facet | Alex S Nicholson David A Priestman Robin Antrobus James C Williamson Reuben Bush Shannon J McKie Henry G Barrow Emily Smith Kostantin Dobrenis Nicholas A Bright Frances M Platt Janet E Deane |
| author_sort | Alex S Nicholson |
| collection | DOAJ |
| description | Glycosphingolipids (GSL) are important bioactive membrane components. GSLs containing sialic acids, known as gangliosides, are highly abundant in the brain and diseases of ganglioside metabolism cause severe early-onset neurodegeneration. The ganglioside GM2 is processed by β-hexosaminidase A and when non-functional GM2 accumulates causing Tay-Sachs and Sandhoff diseases. We have developed i3Neuron-based disease models demonstrating storage of GM2 and severe endolysosomal dysfunction. Additionally, the plasma membrane (PM) is significantly altered in its lipid and protein composition. These changes are driven in part by lysosomal exocytosis causing inappropriate accumulation of lysosomal proteins on the cell surface. There are also significant changes in synaptic protein abundances with direct functional impact on neuronal activity. Lysosomal proteins are also enriched at the PM in GM1 gangliosidosis supporting that lysosomal exocytosis is a conserved mechanism of PM proteome change in these diseases. This work provides mechanistic insights into neuronal dysfunction in gangliosidoses highlighting that these are severe PM disorders with implications for other lysosomal and neurodegenerative diseases. |
| format | Article |
| id | doaj-art-9c39efa0a0e64c5587e349177be697ac |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-9c39efa0a0e64c5587e349177be697ac2025-08-20T03:27:43ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-07-01237e300326510.1371/journal.pbio.3003265Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction.Alex S NicholsonDavid A PriestmanRobin AntrobusJames C WilliamsonReuben BushShannon J McKieHenry G BarrowEmily SmithKostantin DobrenisNicholas A BrightFrances M PlattJanet E DeaneGlycosphingolipids (GSL) are important bioactive membrane components. GSLs containing sialic acids, known as gangliosides, are highly abundant in the brain and diseases of ganglioside metabolism cause severe early-onset neurodegeneration. The ganglioside GM2 is processed by β-hexosaminidase A and when non-functional GM2 accumulates causing Tay-Sachs and Sandhoff diseases. We have developed i3Neuron-based disease models demonstrating storage of GM2 and severe endolysosomal dysfunction. Additionally, the plasma membrane (PM) is significantly altered in its lipid and protein composition. These changes are driven in part by lysosomal exocytosis causing inappropriate accumulation of lysosomal proteins on the cell surface. There are also significant changes in synaptic protein abundances with direct functional impact on neuronal activity. Lysosomal proteins are also enriched at the PM in GM1 gangliosidosis supporting that lysosomal exocytosis is a conserved mechanism of PM proteome change in these diseases. This work provides mechanistic insights into neuronal dysfunction in gangliosidoses highlighting that these are severe PM disorders with implications for other lysosomal and neurodegenerative diseases.https://doi.org/10.1371/journal.pbio.3003265 |
| spellingShingle | Alex S Nicholson David A Priestman Robin Antrobus James C Williamson Reuben Bush Shannon J McKie Henry G Barrow Emily Smith Kostantin Dobrenis Nicholas A Bright Frances M Platt Janet E Deane Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction. PLoS Biology |
| title | Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction. |
| title_full | Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction. |
| title_fullStr | Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction. |
| title_full_unstemmed | Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction. |
| title_short | Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction. |
| title_sort | plasma membrane remodeling in gm2 gangliosidoses drives synaptic dysfunction |
| url | https://doi.org/10.1371/journal.pbio.3003265 |
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