Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 23, Issue 4, Pages 957-964Publisher
WILEY
DOI: 10.1111/j.1460-9568.2006.04631.x
Keywords
caspases; chemokine; CXCL10; HIV-associated dementia; human; neuronal apoptosis
Categories
Funding
- NCRR NIH HHS [P20-RR16443, RR-16443, P20 RR016475] Funding Source: Medline
- NIAID NIH HHS [AI-29382] Funding Source: Medline
- NIMH NIH HHS [MH072355, MH62969-01, MH-068212] Funding Source: Medline
- NINDS NIH HHS [NS-32203] Funding Source: Medline
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Chemokines play a key role in the regulation of central nervous system disease. CXCL10 over-expression has been observed in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease and HIV-associated dementia. More recent studies by others and us have shown that CXCL10 elicits apoptosis in fetal neurons. The mechanism of CXCL10-mediated neurotoxicity, however, remains unclear. In this study, we provide evidence for the direct role of Ca2+ dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca2+ and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca2+ elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca2+, which is available for uptake by the mitochondria, is associated with membrane permeabilization and cytochrome c release from this compartment. The released cytochrome c then activates the initiator active caspase-9. This initiator caspase sequentially activates the effector caspase-3, ultimately leading to apoptosis. This study identifies the temporal signaling cascade involved in CXCL10-mediated neuronal apoptosis and provides putative targets for pharmaceutical intervention of neurological disorders associated with CXCL10 up-regulation.
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