Alpha-synuclein induced cell death in mouse hippocampal (HT22) cells is mediated by nitric oxide-dependent activation of caspase-3.
Our previous studies indicated that exogenous alpha-synuclein (ASN) activates neuronal nitric oxide (NO) synthase (nNOS) in rat brain slices. The present study, carried out on immortalized hippocampal neuronal cells (HT22), was designed to extend the previous results by showing the molecular pathway of NO-mediated cell death induced by exogenous ASN. Extracellular ASN (10 microM) was found to stimulate nitric oxide synthase (NOS) and increase caspase-3 activity in HT22 cells, leading to poly(ADP-ribose) polymerase (PARP-1) cleavage. The inhibitor of Ca2+-dependent NOS (N-nitro-L-arginine, 100 microM) prevented ASN-evoked caspase-3 activation and PARP-1 degradation. ASN exposure resulted in apoptotic death of HT22 cells and this effect was reversed by inhibition of NO synthesis and caspase-3 activity. Our results demonstrated that extracellular ASN induces neuronal cell death by NO-mediated caspase-3 activation.
Adamczyk
Agata
A
Department of Cellular Signaling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. agataz@cmdik.pan.pl
Kaźmierczak
Anna
A
Czapski
Grzegorz Arkadiusz
GA
Strosznajder
Joanna Benigna
JB
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051844:alpha-Synuclein / Q000494:pharmacology*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3