title: Sphingosine-1-phosphate links glycosphingolipid metabolism to neurodegeneration via a calpain-mediated mechanism.
abstract: 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.
authors.affiliation: LIMES Institute Membrane Biology and Lipid Biochemistry, University of Bonn, Bonn 53121, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Hagen
authors.forename: M
authors.initials: M
authors.lastname: Hans
authors.forename: D
authors.initials: D
authors.lastname: Hartmann
authors.forename: D
authors.initials: D
authors.lastname: Swandulla
authors.forename: G
authors.initials: G
authors.lastname: van Echten-Deckert
mesh_terms: D000446:Aldehyde-Lyases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D053454:Caspase 12 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002531:Cerebellum / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D002118:Calcium; D002154:Calpain; D053454:Caspase 12; D053453:Caspase 9; D051360:Cyclin-Dependent Kinase 5; D006028:Glycosphingolipids; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D016875:tau Proteins; D000099157:Sphingosine Kinase; C106700:4-methylsphingosine; C060506:sphingosine 1-phosphate; C022649:sphingosine 1-phosphate lyase (aldolase)