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Abstract

Iron is essential for neurons and glial cells, playing key roles in neurotransmitter synthesis, energy
production and myelination. In contrast, high concentrations of free iron can be detrimental and contribute
to neurodegeneration, through promotion of oxidative stress. Particularly in Parkinson’s disease (PD)
changes in iron concentrations in the substantia nigra (SN) was suggested to play a key role in
degeneration of dopaminergic neurons in nigrosome 1. However, the cellular iron pathways and the
mechanisms of the pathogenic role of iron in PD are not well understood, mainly due to the lack of
quantitative analytical techniques for iron quantification with subcellular resolution. Here, we quantified
cellular iron concentrations and subcellular iron distribution in dopaminergic neurons and different types
of glial cells in the SN both in brains of PD patients and in non-neurodegenerative control brains (Co). To
this end, we combined spatially resolved quantitative element mapping using micro particle induced X-ray
emission (μPIXE) with nickel-enhanced immunocytochemical detection of cell type-specific antigens
allowing to allocate element-related signals to specific cell types. Distinct patterns of iron accumulation
were observed across different cell populations. In the control (Co) SNc, oligodendroglial and astroglial
cells hold the highest cellular iron concentration whereas in PD, the iron concentration was increased in
most cell types in the substantia nigra except for astroglial cells and ferritin-positive oligodendroglial cells.
While iron levels in astroglial cells remain unchanged, ferritin in oligodendroglial cells seems to be
depleted by almost half in PD. The highest cellular iron levels in neurons were located in the cytoplasm,
which might increase the source of non-chelated Fe3+, implicating a critical increase in the labile iron pool.
Indeed, neuromelanin is characterised by a significantly higher loading of iron including most probable the
occupancy of low-affinity iron binding sites. Quantitative trace element analysis is essential to characterise
iron in oxidative processes in PD. The quantification of iron provides deeper insights into changes of
cellular iron levels in PD and may contribute to the research in iron-chelating disease-modifying drugs.