Sphingosine-1-phosphate links glycosphingolipid metabolism to neurodegeneration via a calpain-mediated mechanism
| Autor: | Michael Hans, Dieter Hartmann, Nadine Hagen, Dieter Swandulla, G van Echten-Deckert |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Sphingosine-1-phosphate
Apoptosis tau Proteins Glycosphingolipids chemistry.chemical_compound Mice Sphingosine Cerebellum medicine Animals Molecular Biology Caspase Caspase 12 Ca2+-release Aldehyde-Lyases Mice Knockout Neurons Original Paper cis-4-methylsphingosine biology Calpain Endoplasmic reticulum Neurodegeneration Cell Cycle Neurotoxicity neurodegeneration Cyclin-Dependent Kinase 5 Cell Biology medicine.disease Caspase 9 Cell biology Mitochondria Mice Inbred C57BL Phosphotransferases (Alcohol Group Acceptor) chemistry Biochemistry Nerve Degeneration biology.protein lipids (amino acids peptides and proteins) Calcium Signal transduction Lysophospholipids Signal Transduction |
| Zdroj: | Cell Death and Differentiation |
| ISSN: | 1476-5403 1350-9047 |
| Popis: | We have recently reported that the bioactive lipid sphingosine-1-phosphate (S1P), usually signaling proliferation and anti-apoptosis induces neuronal death when generated by sphingosine-kinase2 and when accumulation due to S1P-lyase deficiency occurs. In the present study, we identify the signaling cascade involved in the neurotoxic effect of sphingoid-base phosphates. We demonstrate that the calcium-dependent cysteine protease calpain mediates neurotoxicity by induction of the endoplasmic reticulum stress-specific caspase cascade and activation of cyclin-dependent kinase5 (CDK5). The latter is involved in an abortive reactivation of the cell cycle and also enhances tau phosphorylation. Neuroanatomical studies in the cerebellum document for the first time that indeed neurons with abundant S1P-lyase expression are those, which degenerate first in S1P-lyase-deficient mice. We therefore propose that an impaired metabolism of glycosphingolipids, which are prevalent in the central nervous system, might be linked via S1P, their common catabolic intermediate, to neuronal death. |
| Databáze: | OpenAIRE |
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