Sphingosylphosphocholine effects on cultured astrocytes reveal mechanisms potentially involved in neurotoxicity in Niemann-Pick type A disease.
Niemann-Pick type A is a disease characterized by the absence of a functional SMPD1 (acidic sphingomyelinase) gene and the abnormal accumulation of sphingomyelin. Under these conditions, also sphingosylphosphocholine (SPC, a sphingomyelin metabolite) accumulates in various tissues, including the brain, where it might act as a toxic stimulus, contributing to the appearance of the neurological symptoms. We studied the effects of SPC on astrocytic and neuronal cultures from rat. In particular, we investigated the possibility that SPC acts on astrocytes and that this represents the first step leading to neurodegeneration. Our results show that acute administration of SPC to astrocytes in culture promotes Ca2+ responses and a release of glutamate that, in turn, leads to cytosolic [Ca2+] elevation in neurons. We also show that chronic stimulation by SPC leads astrocytes to proliferate, but can also change their phenotype towards an activated state that might contribute to the inflammatory responses. Interestingly, upon acute SPC stimulation, activated astrocytes release more glutamate. In conclusion, we show that both chronic and acute exposure to SPC can constitute harmful signals that may have a role in the sequence of events leading to neurodegeneration.
San Raffaele Scientific Institute, via Olgettina 58, I-20132 Milano, Italy.
Nino
N
Chiulli
Franca
F
Codazzi
Alessandra
A
Di Cesare
Claudia
C
Gravaghi
Daniele
D
Zacchetti
Fabio
F
Grohovaz
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D005456:Fluorescent Dyes; D016257:Fura-2; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D018715:Microscopy, Video; D009336:Necrosis / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D052536:Niemann-Pick Disease, Type A / Q000473:pathology*; D010641:Phenotype; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D005456:Fluorescent Dyes; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D018698:Glutamic Acid; D013110:Sphingosine; D016257:Fura-2