Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance

Atrián‐Blasco, Elena; González, Paulina; Santoro, Alice; Aliès, Bruno; Faller, Peter; Hureau, Christelle

doi:10.1016/j.ccr.2018.04.007

Cited by 142 publications

(173 citation statements)

References 221 publications

(285 reference statements)

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“…The activity of ubiquitin proteasome system (UPS) is decreased in the AD brains, and the UPS activity is closely intertwined with autophagy functions. Moreover, the copper, Fe and zinc ions can bind to UPS components, e.g., the proteasome and ubiquitin can and thus modify their activity [94].…”

Section: Role Of Metal Ions In Autophagymentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

295

188

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Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly. Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating βor γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogenactivated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/ subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/ deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

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Section: Role Of Metal Ions In Autophagymentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

295

188

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“…Furthermore, the complexes themselves may be cytotoxic, as, e.g., it was reported to be Cu 2+ /α-syn [60]. The properties of the complex formation between metal ions and α-syn have been reviewed by several authors (e.g., [12,32,60,61]). As regards the binding moiety, it is known that metal ions can bind to high-affinity N-terminal (containing residues 1-60) and to lower affinity C-terminal sites of α-syn (from 96 to 140 amino acid residues).…”

Section: Parkinson's Disease and Metal Ionsmentioning

confidence: 99%

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

Tosato

Marco

2019

Biomolecules

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The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson’s disease (PD) therapy in the year range 2014–2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules. Stoichiometries and stability constants of the complexes have been reported; values of the cologarithm of the concentration of free metal ion at equilibrium (pM), and of the dissociation constant Kd (both computed at pH = 7.4 and at total metal and ligand concentrations of 10–6 and 10–5 mol/L, respectively), charge and stoichiometry of the most abundant metal–ligand complexes existing at physiological conditions, have been obtained. A rigorous definition of the reported amounts is given, the possible usefulness of this data is described, and the need to characterize the metal–ligand speciation of PD drugs is underlined.

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“…[39] Moreover,C ui ons are likely coordinated differently during redox cycling. [40] In conclusion, ACR-modified His in P2 ACR did not significantly impact the ROS productionunder the present conditions.…”

Section: His Modification Does Not Influence Ros Production By Cu 2 +mentioning

confidence: 52%

Acrolein and Copper as Competitive Effectors of α‐Synuclein

Falcone

Ahmed

Oliveri

et al. 2020

Chemistry A European J

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Mounting evidences upports the role of amyloidogenesis, oxidative stress, and metal dyshomeostasis in the development of neurodegenerative disorders. Parkinson's Disease is characterized by a-synuclein (aSyn) accumulation and aggregation in brain regions,a lso promoted by Cu 2 + . aSyn is modified by reactive carbonyl species, including acrolein (ACR). Notwithstanding these findings, the interplay between ACR, copper,a nd aSyn has never been investigated. Therefore, we explored more thoroughly the effects of ACR on aSyn using an approach based on LC-MS/MS analy-sis. We also evaluated the influence of Cu 2 + on the protein carbonylation and how the ACR modification impacts the Cu 2 + binding and the production of Reactive OxygenS pecies (ROS). Finally,w ei nvestigated the effects of ACR and Cu 2 + ions on the aSyn aggregation by dynamic light scattering and fluorescencea ssays. Cu 2 + regioselectively inhibits the modification of His50 by ACR, the carbonylation lowers the affinity of His50 for Cu 2 + and ACR inhibits aSyn aggregation both in the presence and in the absence of Cu 2 + .Supporting information and the ORCID identification numbers for the authors of this article can be found under: https://doi.

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Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance

Cited by 142 publications

References 221 publications

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

Acrolein and Copper as Competitive Effectors of α‐Synuclein

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