Metals associated neurodegeneration in Parkinson’s disease: Insight to physiological, pathological mechanisms and management

Raj, Khadga; Kaur, Pawandeep; Gupta, Gagan; Singh, Shamsher

doi:10.1016/j.neulet.2021.135873

Cited by 103 publications

(75 citation statements)

References 71 publications

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“…This, in turn, might result in a decreased capacity to protect the cell against αSyn aggregation and toxicity. Finally, As(III) and Cd(II) exposure can induce oxidative stress and disrupt ATP generation [ 22 ], which in turn might also impact αSyn biology.…”

Section: Discussionmentioning

confidence: 99%

“…Exposure to heavy metals has been linked to neurodegeneration [ 20 , 21 , 22 ]. Binding of metal ions to disease-associated proteins could not only affect their aggregation speed, but also change the resulting morphology of the fibrils.…”

Section: Introductionmentioning

confidence: 99%

“…The heavy metal cadmium (Cd) and the metalloid arsenic (As) are clearly toxic and classified as human carcinogens [ 30 , 31 ]. Chronic heavy metal exposure, including As and Cd, has been implicated in promoting the progression of certain neurodegenerative and age-related disorders, including PD and AD [ 22 , 31 , 32 , 33 , 34 ]. However, the mechanisms by which As and Cd affect disease processes are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

Lorentzon

Horváth

Kumar

et al. 2021

IJMS

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Exposure to heavy metals, including arsenic and cadmium, is associated with neurodegenerative disorders such as Parkinson’s disease. However, the mechanistic details of how these metals contribute to pathogenesis are not well understood. To search for underlying mechanisms involving α-synuclein, the protein that forms amyloids in Parkinson’s disease, we here assessed the effects of arsenic and cadmium on α-synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human α-synuclein demonstrated that amyloid fibers formed in the presence of the metals have a different fiber pitch compared to those formed without metals. Both metal ions become incorporated into the amyloid fibers, and cadmium also accelerated the nucleation step in the amyloid formation process, likely via binding to intermediate species. Fluorescence microscopy analyses of yeast cells expressing fluorescently tagged α-synuclein demonstrated that arsenic and cadmium affected the distribution of α-synuclein aggregates within the cells, reduced aggregate clearance, and aggravated α-synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and α-synuclein modulate the resulting amyloid fiber structures, which, in turn, might relate to the observed effects in the yeast cells. Whilst our study advances our understanding of how these metals affect α-synuclein biophysics, further in vitro characterization as well as human cell studies are desired to fully appreciate their role in the progression of Parkinson’s disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

Lorentzon

Horváth

Kumar

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…For instance, at least 140 million people in 50 countries have been drinking water containing As at levels above the WHO guideline [ 5 ]. Depending on the period of exposure over a lifetime, environmental metals affect neurodevelopment [ 6 , 7 ], neurobehavior [ 8 ], cognition [ 9 ], or are involved in the etiology of neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. In particular, prenatal and early childhood exposure to environmental metals such as As, Pb, Mn, Cd, or Hg has emerged as strong candidate etiological factors in autism spectrum disorder (ASD) [ 6 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function

Carmona

Roudeau

Ortega

2021

Toxics

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Environmental exposure to neurotoxic metals and metalloids such as arsenic, cadmium, lead, mercury, or manganese is a global health concern affecting millions of people worldwide. Depending on the period of exposure over a lifetime, environmental metals can alter neurodevelopment, neurobehavior, and cognition and cause neurodegeneration. There is increasing evidence linking environmental exposure to metal contaminants to the etiology of neurological diseases in early life (e.g., autism spectrum disorder) or late life (e.g., Alzheimer’s disease). The known main molecular mechanisms of metal-induced toxicity in cells are the generation of reactive oxygen species, the interaction with sulfhydryl chemical groups in proteins (e.g., cysteine), and the competition of toxic metals with binding sites of essential metals (e.g., Fe, Cu, Zn). In neurons, these molecular interactions can alter the functions of neurotransmitter receptors, the cytoskeleton and scaffolding synaptic proteins, thereby disrupting synaptic structure and function. Loss of synaptic connectivity may precede more drastic alterations such as neurodegeneration. In this article, we will review the molecular mechanisms of metal-induced synaptic neurotoxicity.

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“…Dyshomeostasis of physiological metal ions is a common feature of neurological disorders such as AD [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Studies report that higher levels of metal ions, such as Cu 2+ , Zn 2+ and Fe 3+ , are found in cerebral amyloid plaques of AD patients compared to the concentrations detected in the brains of non-AD patients [ 13 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents

et al. 2021

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Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.

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Metals associated neurodegeneration in Parkinson’s disease: Insight to physiological, pathological mechanisms and management

Cited by 103 publications

References 71 publications

Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function

Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents

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