Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus: evidence in Parkinson's disease patients.
We show that intranigral lipopolysaccharide (LPS) injection, which provokes specific degeneration of DA neurons, induced caspase-3 activation in the rat ventral mesencephalon, which was mostly associated with glial cells. In contrast, nigral DA neurons exhibited AIF nuclear translocation in response to LPS. A significant decrease of the Bcl-2/Bax ratio in nigral tissue after LPS injection was observed. We next developed an in vitro co-culture system with the microglial BV2 and the DA neuronal MN9D murine cell lines. The silencing of caspase-3 or AIF by small interfering RNAs exclusively in the DA MN9D cells demonstrated the key role of AIF in the LPS-induced death of DA cells. In vivo chemical inhibition of caspases and poly(ADP-ribose)polymerase-1, an upstream regulator of AIF release and calpain, proved the central role of the AIF-dependent pathway in LPS-induced nigral DA cell death. We also observed nuclear translocation of AIF in the ventral mesencephalon of Parkinson's disease subjects.
Burguillos
M A
MA
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Spain.
Hajji
N
N
Englund
E
E
Persson
A
A
Cenci
A M
AM
Machado
A
A
Cano
J
J
Joseph
B
B
Venero
J L
JL
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004298:Dopamine / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology
D051033:Apoptosis Inducing Factor; D008070:Lipopolysaccharides; C494830:AIFM1 protein, mouse; D004298:Dopamine