Jolanta Galazka-Friedman

Ferritin as an important player in neurodegeneration.

Oxidative stress is considered one of the pathways leading to neuronal death in neurodegenerative disease. Many published studies aimed to assess the possible role of iron in this process but no consensus has been reached. On the other hand little is known about the role played by the main iron storage protein - ferritin. In this review we discuss the data obtained using several methods - Mössbauer spectroscopy, electron microscopy and ELISA - from human brain tissue both in controls and in four neurodegenerative disorders - Parkinsons (PD) and Alzheimers disease, progressive supranuclear palsy and neuroferritinopathy. Iron may only cause oxidative stress injury when it is available as labile iron for Fenton reaction. This may be related to the decreased ability of ferritin to retain iron within the iron core of ferritin. This happens in PD and in neuroferritinopathy. In PD there is a decrease in the concentration of L ferritin, while in neuroferritinopathy there is a genetically induced mutation in L ferritin causing its loss of function. We discuss the importance of the ratio H/L ferritin and its changes in neurodegeneration.

Iron and reactive oxygen species activity in parkinsonian substantia nigra

OBJECTIVES We sought to determine concentrations of total and labile iron in substantia nigra from patients with Parkinson disease and from controls to assess if oxidative stress is triggered by an increased concentration of iron. METHODS Total iron concentration in the whole substantia nigra was evaluated in 17 parkinsonian and 29 control samples. Concentrations of labile iron and copper were assessed in 6 parkinsonian and 8 control samples. The total iron concentration, the Fe(2+)/Fe(3+) ratio, and iron-binding compounds were determined by Mössbauer spectroscopy. Labile iron and copper were measured by electrothermal atomic absorption spectrometry. Activity of reactive oxygen species was evaluated by visible light fluorescence. RESULTS The labile iron concentration was significantly higher and corresponded to significantly higher reactive oxygen species activity in parkinsonian vs control samples. No significant difference was found in the total concentrations of copper or iron in the whole substantia nigra between parkinsonian and control samples. Mössbauer spectroscopy detected no Fe(2+) in any samples. CONCLUSIONS The substantia nigra of parkinsonian patients contained more labile iron compared with that of controls. This labile iron generated higher reactive oxygen species activity. The oxidative stress damage in parkinsonian substantia nigra may be related to an excess of labile iron and not of the total iron in the diseased tissue.

Iron as a cause of Parkinson disease - a myth or a well established hypothesis?

Iron is considered to be a possible trigger of oxidative stress leading to neurodegeneration. This mechanism of neuronal death is proposed as a cause of Parkinson disease. Although most of researchers agree with this, controversies remain regarding the amounts of iron needed for this process. According to non destructive methods of assessment of the concentration of the total iron in substantia nigra, there is no difference between PD and control. However there is no need for an increase of the total iron in parkinsonian SN to trigger the oxidative stress but only of the non-ferritin bound labile iron. Our recent studies suggest an increase of this iron in PD SN. This finding corresponds well to a decrease of L-ferritin concentration in parkinsonian SN and also to a difference of the size of iron core of ferritin between PD and control SN. The significance of these finding will be discussed.

Does iron play a role in Parkinson's disease?

Mössbauer studies of Parkinsonian and control Substantia Nigra (SN) show that the overall amount of iron in SN is about the same in PD and control. At least 90% of this iron is ferritin-like and Fe2+ and/or neuromelanin iron, if present at all, can constitute only less than 10% of the overall iron. During storage in formalin, iron is slowly removed from ferritin and bound to a chelating agent.

The history of the research of iron in parkinsonian substantia nigra

The role of iron in pathogenesis of Parkinson’s disease is widely discussed in the literature. The authors present the history of studies of iron in parkinsonian tissue from the substantia nigra.

Mössbauer spectroscopy and the iron on Mars

Both the USSR and US have plans of performing rover missions and sample return missions to the planet Mars in the coming decade. There may be possibilities of performingin situ Mössbauer spectroscopy on Mars or on fresh samples returned to a space station.

The role of iron in neurodegeneration--Mössbauer spectroscopy, electron microscopy, enzyme-linked immunosorbent assay and neuroimaging studies.

The possible role of iron in neurodegeneration was studied by various techniques: electron microscopy, enzyme-linked immunosorbent assay, Mössbauer spectroscopy, atomic absorption, ultrasonography and magnetic resonance imaging. The measurements were made on human tissues extracted from liver and from brain structures involved in diseases of the human brain: substantia nigra (Parkinsons, PD), hippocampal cortex (Alzheimers, AD) and globus pallidus (progressive supranuclear palsy, PSP). The sizes of the iron cores of ferritin, the main iron storage compound in tissues, were found to be smaller in brain than in liver. Brain ferritin has a higher proportion of H to L chains compared to liver. A significant decrease of the concentration of L chains in PD compared to control was found. No increase in the concentration of iron in PD versus control was detected; however, there was an increase of labile iron, which constitutes only 2‰ of brain iron. In AD an increase in the concentration of ferritin was noticed, without a significant increase in iron concentration. In PSP an increase of total iron was observed. Our findings suggest that the mechanisms leading to the death of nerve cells in these three diseases may be different, although all may be related to iron mediated oxidative stress.

Iron as a trigger of neurodegeneration in Parkinson's disease.

Publisher Summary Iron plays an important role in all living cells and is essential for many metabolic functions in the central nervous system (CNS). The concentration of iron in human substantia nigra (SN) increases with aging up to the third decade and then levels off. In oxidative reactions in the CNS, as in any other tissue, iron generates free radicals via the Fenton reaction. Free radicals, produced in this process, are neutralized under normal conditions by free radical scavengers. It is the excess of free radicals, caused either by an increase in production of free radicals or by decreased abilities to neutralize them, which become a starting point for oxidative stress. Broken iron homeostasis in SN is therefore the trigger for neurodegeneration, leading to Parkinsons disease (PD). The causes of this broken iron homeostasis are related to a change in iron concentration, a change in the iron redox state or a change in the forms of iron binding.

Iron and ferritin in hippocampal cortex and substantia nigra in human brain — Implications for the possible role of iron in dementia

The concentrations of iron and of ferritin, the main iron-binding compound in the brain, as well as the sizes of the iron cores of ferritin were assessed in hippocampal cortex (Hip) and substantia nigra (SN) from human control brains, using Mössbauer spectroscopy (MS), ELISA and electron microscopy. 8 Hip and 20 SN samples were measured by MS, 11 Hip and 11 SN were used for ELISA, and the size of the iron cores of ferritin was assessed from measurements of 50 iron cores from Hip-ferritin and 50 iron cores from SN-ferritin. The average concentration of iron in Hip was found to be about one third of that in SN, as was the concentration of H-ferritin, yet L-ferritin was less than one fifth in Hip compared to SN. The size of the average iron core in Hip was assessed to be about 3.1 nm and about 3.7 nm in SN. These results may point to different iron metabolism in these areas, suggesting faster iron turnover in Hip.

Iron in Parkinson's Disease Revisited

Mössbauer studies of fresh frozen samples taken at autopsy from different parts of the human brain (globus pallidus (GP), substantia nigra (NS), and hippocamp (Hip)) showed a relatively high concentration of iron in these structures. Mössbauer data, biochemical results and transmission electron micrographs lead to the conclusion that in all above-mentioned structures iron is located mainly within ferritin. However, the Mössbauer doublets obtained from most brain samples at 90 K are slightly asymmetric. This asymmetry could be caused by the presence of a small amount of non-ferritin-like iron. Measurements at 4.1 K showed besides the six-line spectra characteristic for ferritin-like iron, an additional doublet with Mössbauer parameters different from ferritin. We found a slightly higher asymmetry and intensity of the 4.1 K doublet in Mössbauer spectra of Parkinsonian SN than in control SN. As Parkinsons disease is a progressive degeneration of nervous cells in SN and iron may be involved in this degeneration process, this may suggest that the factors evoking these phenomena are related to the pathogenesis of Parkinsons disease.