Copper binding and protein aggregation: a journey from the brain to the human lens

Posadas, Yanahi; Sánchez-López, Carolina; Quintanar, Liliana

doi:10.1039/d3cb00145h

Cited by 3 publications

(8 citation statements)

References 103 publications

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“…This is different from the formation of fibril when γD-Crystallin is exposed to UV−C light. 5 ANS binding studies were carried out to get more details about the effect of Cu (II) on γD-Crystallin. A globular protein has hydrophobic regions buried deep inside a folded state.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Our earlier results have shown that encapsulation of quercetin increases its shelf life. 5 To further confirm that quercetin-loaded nanocarriers can act as inhibitors, TEM was employed. The TEM micrographs in the So far, it could be concluded that metal ions like Cu (II) bind with γD-Crystallin.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Cataracts can be of various types based on their etiology. 5 A congenital cataract is the result of mutations in genes, most of them being hereditary. 6 On the other hand, age-related cataract, also known as senile cataract, results from factors such as smoking and exposure to oxidative stress.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Cataracts can be of various types based on their etiology . A congenital cataract is the result of mutations in genes, most of them being hereditary .…”

Section: Introductionmentioning

confidence: 99%

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Quercetin-Loaded Nanocarriers as Effective Inhibitors for Copper Metal Ion-Induced γD-Crystallin Aggregation

Goswami,

Das,

Deep

2024

Langmuir

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Cataract is one of the leading causes of blindness worldwide. Till date, the only solution for cataracts is surgery, which is a resource-intensive solution. A much simpler solution is to find a potential drug that could inhibit aggregation. It is well established that nonamyloid aggregates of eye lens protein result in cataract. γD-Crystallin, a thermodynamically stable protein, is one of the most abundant proteins in the core of the eye lens and is found to aggregate under stress conditions, leading to the cataract. It has also been found that in cataractous lens, the concentration of metals like copper is elevated significantly as compared to healthy eye lens, suggesting their role in inducing aggregation. In our present study, aggregation of γD-Crystallin was carried out in the presence of Cu (II). Using techniques like turbidity assay, CD spectroscopy, ANS binding assay, and microscopic studies like TEM, it could be confirmed that protein aggregates in the presence of Cu (II) and the nature of aggregates is amorphous. Various polyphenols were tested to suppress aggregation of the protein. Quercetin was observed to be the most efficient. To overcome the problems associated with the delivery of polyphenols, such as solubility and bioavailability, quercetin was encapsulated in two types of nanocarriers. Their characterization was done using TEM, DLS, and other techniques. The potency of quercetin-loaded CS-TPP/ CS-PLGA NPs as inhibitors of γD-Crystallin aggregation was confirmed by various experiments.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

“…Cataracts can be of various types based on their etiology . A congenital cataract is the result of mutations in genes, most of them being hereditary .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Quercetin-Loaded Nanocarriers as Effective Inhibitors for Copper Metal Ion-Induced γD-Crystallin Aggregation

Goswami,

Das,

Deep

2024

Langmuir

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“…Although the protective effect of Cu(II) on amyloid aggregation of both pathogenic and nonpathogenic proteins has been reported, Cu(II) is also known to promote amyloid formation of different proteins. − For example, several research studies suggest that Cu(II) ions can enhance the amyloid aggregation of Aβ 1–40 , immunoglobulin G (IgG), and BSA . However, the inhibitory effect of Cu(II) ion has also been established against the aggregation of several pathogenic proteins and peptides including amylin, Aβ 1–16 , Aβ 1–42 , and γD-crystalline. − Although an altered level of Cu(II) has been reported in the brains of AD patients which can directly influence senile plaque deposition and neuronal loss, as well as neuroinflammation, a direct link between copper and the neurotoxicity in AD is largely unexplored. Some studies have shown Cu(II) deficiency in the pathogenesis of AD, while other reports have revealed increased Cu(II) content .…”

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confidence: 99%

Cu(II) Specifically Disassembles Insulin Amyloid Nanostructures via Direct Interaction with Cross-β Fibrils

Mittal,

Prajapati,

Ansari

et al. 2024

Nano Lett.

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In this work, we demonstrate direct evidence of the antiamyloid potential of Cu(II) ions against amyloid formation of insulin. The Cu(II) ions were found to efficiently disassemble the preformed amyloid nanostructures into soluble species and suppress monomer fibrillation under aggregation-prone conditions. The direct interaction of Cu(II) ions with the cross-β structure of amyloid fibrils causes substantial disruption of both the interchain and intrachain interactions, predominantly the H-bonds and hydrophobic contacts. Further, the Cu(II) ions show a strong affinity for the aggregation-prone conformers of the protein and inhibit their spontaneous self-assembly. These results reveal the possible molecular mechanism for the antiamyloidogenic potential of Cu(II) which could be important for the development of metal-ion specific therapeutic strategies against amyloid linked complications.

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Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Min,

Sarlus,

Harris

2024

Front. Mol. Neurosci.

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The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.

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Copper binding and protein aggregation: a journey from the brain to the human lens

Abstract: Metal ions have been implicated in several proteinopathies associated to degenerative and neurodegenerative diseases. While the molecular mechanisms for protein aggregation are still under investigation, recent findings from CryoEM point...

Cited by 3 publications

References 103 publications

Quercetin-Loaded Nanocarriers as Effective Inhibitors for Copper Metal Ion-Induced γD-Crystallin Aggregation

Quercetin-Loaded Nanocarriers as Effective Inhibitors for Copper Metal Ion-Induced γD-Crystallin Aggregation

Cu(II) Specifically Disassembles Insulin Amyloid Nanostructures via Direct Interaction with Cross-β Fibrils

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

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