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The Iron-Binding Protein Lactoferrin Protects Vulnerable Dopamine Neurons from Degeneration by Preserving Mitochondrial Calcium Homeostasis.
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Mol Pharmacol 2013 Sep;
Authors: Erwann Rousseau, Patrick P Michel, Etienne C Hirsch
Institut du Cerveau et de la Moelle Epinere;
Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is up-regulated in dopamine (DA) neurons resistant to degeneration in Parkinson disease (PD). To study how this could possibly relate to disease progression, we used midbrain cultures and experimental settings that model the progressive loss of DA neurons in this disorder. Human lactoferrin of either recombinant or natural origin provided robust protection to vulnerable DA neurons in a culture paradigm where these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of GDNF, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans onto the cell surface of DA neurons and subsequently to partial inactivation of focal adhesion kinase (FAK), a major effector kinase of integrins. We established that FAK inactivation served to unmask a prosurvival phosphoinositide 3-kinase (PI3K)/AKT-dependent signaling pathway that stimulates calcium shuttling from endoplasmic reticulum to mitochondria. DA neurons exposed to the mitochondrial toxin 1-methyl-4-phenylpyridinium were also partially protected by lactoferrin, comforting the view that mitochondria may represent a downstream target for lactoferrin protective actions. Finally, we found that the iron binding capability of lactoferrin intervened in DA cell rescue, only when neurodegeneration was consecutive to iron-catalyzed oxidative stress. Overall, our data suggest that the accumulation of lactoferrin in PD brains might be evidence of an attempt by the brain to minimize the consequences of neurodegeneration.
PMID: 24077968 [PubMed - as supplied by publisher]