Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus Evidence in Parkinson's disease patients

NEUROBIOLOGY OF DISEASE

卷:41

Article

Burguillos, M. A.^1,2,6  Hajji, N.^2,3  Englund, E.⁴  Persson, A.⁴  Cenci, A. M.⁵  Machado, A.^1,7  Cano, J.^1,7  Joseph, B.²  Venero, J. L.^1,7 

[1] Univ Seville, Fac Farm, Dept Bioquim & Biol Mol, E-41012 Seville, Spain

[2] Karolinska Inst, CCK, Dept Oncol Pathol, SE-17176 Stockholm, Sweden

[3] Univ London Imperial Coll Sci Technol & Med, Div Investigat Sci, Dept Expt Med & Toxicol, London, England

[4] Univ Lund Hosp, Div Neuropathol, Dept Pathol, S-22185 Lund, Sweden

[5] BMC F11, Basal Ganglia Pathophysiol Unit, Dept Expt Med Sci, S-22184 Lund, Sweden

[6] Wallenberg Neurosci Ctr, Dept Expt Med Sci, Neuronal Survival Unit, Lund, Sweden

[7] Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain

关键词: Apoptosis-inducing factor;    Caspase 3;    Apoptosis;    Parkinson's disease;    Substantia nigra;    Dopamine;   

DOI  :  10.1016/j.nbd.2010.09.005

来源: Elsevier

【 摘 要 】

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. CO 2010 Elsevier Inc. All rights reserved.

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