Is Parkinson's disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration?
Razor sharp and high iron deposits are present in the substantia nigra (SN). Although the function of such high iron content is not known, the homeostasis of brain iron is important for normal brain function. The participation of free tissue iron in oxidative stress (OS), resulting in the formation of cytotoxic hydroxyl radical (.OH) from H2O2 (Fenton reaction) and promotion of membrane lipid peroxides by .OH can no longer be questioned as a biological phenomenon. The highly selective increase of Fe2+ and Fe3+ and lipid peroxidation observed in parkinsonian SN points to OS in such brains. Lipid peroxidation proceeds with either Fe2+ or Fe3+ provided a mechanism exists to facilitate the interconversion of iron between its redox states. Indeed H2O2 derived from MAO B reaction and autooxidation of dopamine to melanin in the SN can drive the iron dependent Fenton reaction. Furthermore, interaction of iron with melanin may be even more important considering that melanin avidly binds Fe3+ and reduce it to Fe2+, resulting in .OH generation. Thus, without evoking environmental neurotoxins, the excessive accumulation of free iron in the SN and "melanin-trap" could be the trigger for accelerated cell death and Parkinsonism.
Youdim
M B
MB
Technion-Faculty of Medicine, Rappaport Family Research Institute, Haifa, Israel.
Ben-Shachar
D
D
Riederer
P
P
D006801:Humans; D007501:Iron / Q000378:metabolism*; D008543:Melanins / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*
D008543:Melanins; C014121:neuromelanin; D007501:Iron