title: Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus: evidence in Parkinson's disease patients.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Burguillos
authors.forename: N
authors.initials: N
authors.lastname: Hajji
authors.forename: E
authors.initials: E
authors.lastname: Englund
authors.forename: A
authors.initials: A
authors.lastname: Persson
authors.forename: A M
authors.initials: AM
authors.lastname: Cenci
authors.forename: A
authors.initials: A
authors.lastname: Machado
authors.forename: J
authors.initials: J
authors.lastname: Cano
authors.forename: B
authors.initials: B
authors.lastname: Joseph
authors.forename: J L
authors.initials: JL
authors.lastname: Venero
mesh_terms: 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
chemical_list: D051033:Apoptosis Inducing Factor; D008070:Lipopolysaccharides; C494830:AIFM1 protein, mouse; D004298:Dopamine