Abstract
Sub-cellular trace element quantifications of nano-heterogeneities in brain tissues offer unprecedented ways to explore at elemental level the interplay between cellular compartments in neurodegenerative pathologies. We designed a quasi-correlative method for analytical nanoimaging of the substantia nigra, based on transmission electron microscopy and synchrotron X-ray fluorescence. It combines ultrastructural identifications of cellular compartments and trace element nanoimaging near detection limits, for increased signal-to-noise ratios. Elemental composition of different organelles is compared to cytoplasmic and nuclear compartments in dopaminergic neurons of rat substantia nigra. They exhibit 150–460 ppm of Fe, with P/Zn/Fe-rich nucleoli in a P/S-depleted nuclear matrix and Ca-rich rough endoplasmic reticula. Cytoplasm analysis displays sub-micron Fe/S-rich granules, including lipofuscin. Following AAV-mediated overexpression of α-synuclein protein associated with Parkinson’s disease, these granules shift towards higher Fe concentrations. This effect advocates for metal (Fe) dyshomeostasis in discrete cytoplasmic regions, illustrating the use of this method to explore neuronal dysfunction in brain diseases.
Highlights
Sub-cellular trace element quantifications of nano-heterogeneities in brain tissues offer unprecedented ways to explore at elemental level the interplay between cellular compartments in neurodegenerative pathologies
In brain tissue affected by Parkinson’s disease, little is known about the cellular compartments that contribute to metal dyshomeostasis, higher Fe concentrations have been mainly observed in the soluble fraction extracted from the substantia nigra[22]
Several histological structures including neuronal cell bodies were revealed in the substantia nigra by nano-XRF
Summary
Sub-cellular trace element quantifications of nano-heterogeneities in brain tissues offer unprecedented ways to explore at elemental level the interplay between cellular compartments in neurodegenerative pathologies. Following AAV-mediated overexpression of α-synuclein protein associated with Parkinson’s disease, these granules shift towards higher Fe concentrations This effect advocates for metal (Fe) dyshomeostasis in discrete cytoplasmic regions, illustrating the use of this method to explore neuronal dysfunction in brain diseases. Abnormal levels of iron and copper have been reported in cases of Parkinson’s disease, mainly observed in the substantia nigra, a region of the ventral midbrain which is selectively vulnerable to the underlying pathology[14,15,16,17] These histopathological manifestations of neurodegenerative processes may reflect metal dyshomeostasis linked to mitochondrial and lysosomal dysfunctions[18], contributing to cell death via mechanisms such as ferroptosis[19,20,21]. Both low elemental count-rates as well as low contrasts at the minimal detection limits of various elements, prevented from extracting robust areas for the elemental maps
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