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.

Research Highlights► Intranigral LPS fails to induce caspase 3 in the neuronal dopaminergic population. ► Degenerating dopaminergic neurons showed nuclear localisation of AIF. ► PARP-1 or calpain inhibition protects dopaminergic neurons against LPS. ► AIF silencing protects MN9D cells in co-culture with BV2 cells against LPS. ► Parkinson’s disease subjects showed nuclear AIF in nigral dopaminergic neurons.