Inhibition of GM3 synthase attenuates neuropathology of Niemann-Pick disease Type C. by affecting sphingolipid metabolism
| Autor: | Hee Kyung Jin, Edward H. Schuchman, Yong Chul Bae, Jae-sung Bae, Hyun Lee, Nozomu Okino, Tadashi Yamashita, Song Hyun Yang, Jong Kil Lee |
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| Rok vydání: | 2013 |
| Předmět: |
GM3
medicine.medical_specialty Transgene Mice Transgenic Neuropathology Biology medicine.disease_cause Pathogenesis Internal medicine Cerebellum medicine Animals G(M3) Ganglioside Humans Molecular Biology Cerebrum Cells Cultured Research Articles Mutation Mice Inbred BALB C neuropathology Niemann–Pick disease type C Ganglioside sphingolipids Niemann-Pick Disease Type C Cell Biology General Medicine medicine.disease Sphingolipid Sialyltransferases Niemann-pick type C disease carbohydrates (lipids) Disease Models Animal Endocrinology Immunology lipids (amino acids peptides and proteins) Niemann–Pick disease Gene Deletion |
| Zdroj: | Molecules and Cells |
| ISSN: | 0219-1032 |
| Popis: | In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NPC mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy. |
| Databáze: | OpenAIRE |
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