Copper, iron, and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, transport, distribution and regulation)

Kozłowski, Henryk; Janicka-Kłos, Anna; Brasuń, Justyna; Gaggelli, Elena; Valensin, Daniela; Valensin, Gianni

doi:10.1016/j.ccr.2009.05.011

Cited by 420 publications

(274 citation statements)

References 237 publications

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“…1C). Importantly, the effect of Cu 2+ on the H50Q aSyn mutant appears to be specific to this cation, because other relevant transition metals (24) did not induce the formation of aSyn inclusions (SI Appendix, Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

“…After the exogenous addition of this cation, H50Q aSyn was the only mutant exhibiting intracellular accumulation. The interplay between this variant and Cu 2+ was highly specific, because upon testing other relevant metals (24), no H50Q aSyn inclusions were observed. This unique synergy is not surprising, considering that the N-terminal region of aSyn in which H50 acts as a key metal anchoring residue constitutes the preferential binding interface for Cu 2+ (28,26,33,42).…”

Section: Discussionmentioning

confidence: 99%

“…PD is characterized by the accumulation of aSyn + fibrillar inclusions, and is associated with an imbalance in metal ion homeostasis (e.g., Cu, Zn, and Fe) (24). In the present study we first screened the effect of Cu 2+ over different disease-associated aSyn mutants.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, deregulation of metal homeostasis, including copper, manganese, zinc, iron, and lead, is characteristic of these disorders (23,24). However, there is still no unequivocal evidence for a causative role of metals in synucleinopathies.…”

Section: Significancementioning

confidence: 99%

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Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells have therefore developed a sophisticated machinery for controlling metal-ion homeostasis. However, a breakdown of these mechanisms, or absorption of metals with no known biological function, alter the ionic balance and can result in a disease state, including several neurodegenerative disorders such as AD (21). Understanding the complex structural and functional interactions of metal ions with the various intracellular and extracellular components of the central nervous system, under normal conditions and during neurodegeneration, is essential for the development of effective therapies.…”

Section: Metal Homeostasis In Alzheimer's Diseasementioning

confidence: 99%

Metal ions, Alzheimer's disease and chelation therapy

Budimir¹

2011

Acta Pharmaceutica

179

113

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Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, clinically characterized by memory and cognitive dysfunctions. It is primarily a disease of old age (1) and is the most prevalent cause of dementia in elderly people (2). AD affects about 35 million people worldwide today (3) and it is estimated to nearly double every 20 years, to reach 66 million in 2030, and 115 million in 2050 (3). There is no known cause and no cure for AD and these numbers makes finding a cure or rational treatment for AD an urgent priority. Despite significant advances in understanding the neuropathological and neurochemical events taking place in AD, the etiopathogenesis of progressive and mental cognitive dysfunction associated with aging remains largely unclear.Pathologically, AD is characterized by neuronal degeneration. The brains of AD patients are mainly characterized by extracellular proteic (or neuritic) deposits (amyloid or senile plaques) surrounded by dystrophic neuritic and intracellular neurofibrillary tangles (NFT) (4). The plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behavior such as the entorhinal cortex, hippocam- In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

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Rational Design of Copper and Iron Chelators to Treat Wilson's Disease and Hemochromatosis

Gateau¹,

Mintz²,

Delangle³

2014

Ligand Design in Medicinal Inorganic Chemistry

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Copper, iron, and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, transport, distribution and regulation)

Cited by 420 publications

References 237 publications

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Metal ions, Alzheimer's disease and chelation therapy

Rational Design of Copper and Iron Chelators to Treat Wilson's Disease and Hemochromatosis

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