Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus

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...

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Bibliographic Details
Published in:Neurobiology of disease 2011, Vol.41 (1), p.177-188
Main Authors: Burguillos, M.A, Hajji, N, Englund, E, Persson, A, Cenci, A.M, Machado, A, Cano, J, Joseph, B, Venero, J.L
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis-inducing factor
Caspase 3
Dopamine
Neurology
Parkinson's disease
Substantia nigra
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Summary: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.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2010.09.005