The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis.
Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is upregulated 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 in which these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of glial cell line-derived neurotrophic factor, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans on 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/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, further supporting 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.
Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche (UMR) S975, Institut du Cerveau et de la Moelle Epinière, Paris, France; Institut National de la Santé et de la Recherche Médicale, U975, Paris, France; and Centre National de la Recherche Scientifique, UMR 7225, Paris, France.
Erwann
E
Rousseau
Patrick P
PP
Michel
Etienne C
EC
Hirsch
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
D051100:Glial Cell Line-Derived Neurotrophic Factor; D011994:Recombinant Proteins; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; D007781:Lactoferrin; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium; D004298:Dopamine