Subcellular Localization of Copper—Cellular Bioimaging with Focus on Neurological Disorders
Abstract
:1. Physiology of Copper
1.1. General Physiological Aspects
1.2. Copper Metabolism and Pathways
1.3. Cellular Distribution of Copper
1.3.1. General Cellular Copper Homeostasis
1.3.2. Cellular Copper Homeostasis in the Brain
1.4. Homeostasis and Connection to Other Essential Elements
1.4.1. Iron
1.4.2. Zinc
2. Toxicology of Copper
2.1. Cellular Mechanisms
2.2. Copper-Related Diseases with Focus on Neurological Disorders
2.2.1. Alzheimer’s Disease
2.2.2. Wilson Disease
2.2.3. Pending Objectives—Investigation of Key Players
3. Current Research Interests
4. Analytics of Copper in Cells
4.1. Sample Preparation
4.1.1. Fixation
Chemical Fixation
Cryofixation by Plunge Freezing and High-Pressure Freezing
4.1.2. Dehydration
4.1.3. Embedding and Sectioning
4.2. Element- and Molecule-Specific Bioimaging Techniques
4.2.1. LA-ICP-MS (Laser Ablation Inductively Coupled Plasma Mass Spectrometry)
4.2.2. ToF-SIMS (Time-of-Flight-Secondary Ion Mass Spectrometry)
4.2.3. TEM/X-EDS (Transmission Electron Microscopy Coupled with Energy-Dispersive X-ray Spectroscopy)
4.2.4. Synchrotron-Based XRF (X-ray Fluorescence Spectroscopy)
4.2.5. NanoSIMS (Nano Secondary Ion Mass Spectrometry)
4.3. Bioimaging Applications with Focus on Copper-Related Diseases
5. Future Developments and Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AAS | atomic absorption spectroscopy |
APP | amyloid precursor protein |
ATOX-1 | human antioxidant protein-1 |
BBB | blood-brain barrier |
BLB | blood-liquor barrier |
CCS | copper chaperone for superoxide dismutase 1 |
COX17 | copper chaperone for cytochrome c-oxidase |
CSF | cerebrospinal fluid |
Ctr1 | copper transporter receptor 1 |
Ctr2 | copper transporter receptor 2 |
DMT1 | divalent metal ion transporter |
EXAFS | extended X-ray absorption fine structure |
GSH | glutathione |
ICP-MS | inductively coupled plasma mass spectrometry |
LA-ICP-MS | laser ablation inductively coupled plasma mass spectrometry |
MT | metallothionein |
NanoSIMS | nano secondary ion mass spectrometry |
PrP | prion protein |
ROS | reactive oxygen species |
S-XRF | synchrotron-based X-ray fluorescence spectroscopy |
TEM | transmission electron microscopy |
ToF-SIMS | time-of-flight-secondary ion mass spectrometry |
XANES | X-ray absorption near-edge structure |
XAS | X-ray absorption spectroscopy |
X-EDS | energy-dispersive X-ray spectroscopy |
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Technique | LA-ICP-MS [103,107,108,109,110] | ToF-SIMS [95,111,112] | NanoSIMS [89,100,103,105,113,114] | TEM/X-EDS [103,115,116] | Synchrotron-Based XRF [103,117,118] |
---|---|---|---|---|---|
Beam | Photons | Ions | Ions | Electrons | X-rays |
Spatial Resolution | 2–5 µm | 100–500 nm | 40–50 nm | 0.2 nm for structural imaging 5 nm for elemental mapping | 20 nm |
Sensitivity | low µg/kg range | mg–µg/kg range | mg–µg/kg range | 100–1000 mg/kg | mg–µg/kg range |
Dynamic Range | 109 | 107 | 102 | - | 103 |
Advantage | - simple sample preparation - less matrix effects - no vacuum required - high sample throughput - quantitative analysis - isotope and multi-element analysis (preferably metals) - excellent sensitivity | - highly sensitive - multi-element analysis (detection of all different ions in parallel) - analysis of organic molecules | - high spatial resolution - isotope and multi-element analysis (nonmetals, metalloids, metals) | - structural imaging - more sensitive for metals | - simple sample preparation (can be analyzed in still hydrated and frozen state) - detailed information on oxidation states/element species/ligands - quantitative analysis - more sensitive for metals |
Disadvantage | - lower spatial resolution - mainly limited to metals - destructive analysis | - charge compensation required for insulated biological samples | - elaborated sample preparation - needs high-vacuum conditions - no live-cell analysis - no quantification due to large matrix effects - destructive analysis | - needs high-vacuum conditions - lower sensitivity - qualitative rather than quantitative analysis | - no isotope analysis |
Preferred Sample Characteristics | biological tissue or planar sections (5–100 µm) sample can be hydrated and frozen (use of cryogenic cell) | planar sections (10–20 µm) sample can be hydrated and frozen (use of cryostage) | thin, planar sections (300–400 nm) | thin, planar sections (70–150 nm) | planar sections (50–100 µm) sample can be hydrated and frozen (use of cryostage) |
Sample Preparation | - frozen and hydrated sample is placed on grids but can also be embedded in resin | - fixated sample is typically placed on grids/sample holder - cryofixation or freeze-fracturing - metal coating (e.g., Au, Pt, Ag) may be necessary to avoid charging effects | - dehydrated and fixated sample is typically placed on wafers - chemical fixation/dehydration/resin embedding - cryofixation/freeze-substitution/freeze-drying/resin embedding - metal coating (e.g., Au, Pt, Ag) may be necessary to avoid charging effects | - dehydrated and fixated sample is typically placed on grids - chemical fixation/dehydration/resin embedding - cryofixation/freeze-substitution/freeze-drying/resin embedding | - frozen and hydrated sample is placed on grids/sample holder |
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Witt, B.; Schaumlöffel, D.; Schwerdtle, T. Subcellular Localization of Copper—Cellular Bioimaging with Focus on Neurological Disorders. Int. J. Mol. Sci. 2020, 21, 2341. https://doi.org/10.3390/ijms21072341
Witt B, Schaumlöffel D, Schwerdtle T. Subcellular Localization of Copper—Cellular Bioimaging with Focus on Neurological Disorders. International Journal of Molecular Sciences. 2020; 21(7):2341. https://doi.org/10.3390/ijms21072341
Chicago/Turabian StyleWitt, Barbara, Dirk Schaumlöffel, and Tanja Schwerdtle. 2020. "Subcellular Localization of Copper—Cellular Bioimaging with Focus on Neurological Disorders" International Journal of Molecular Sciences 21, no. 7: 2341. https://doi.org/10.3390/ijms21072341