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Metal Ions and Neurodegenerative Disorders

Error rating book. Refresh and try again. Open Preview See a Problem? Details if other :. Thanks for telling us about the problem. Return to Book Page. Brain Diseases and Metalloproteins by David R. This book describes the latest research on neurodegenerative disease and metal-binding proteins. It lays strong emphasis on biochemistry and cell biology. The diseases covered in the book include Parkinson s disease, Alzheimer s disease, prion disease, and ALS.

The chapters separately examine such issues as mechanisms of metal binding, metal-induced structural changes in p This book describes the latest research on neurodegenerative disease and metal-binding proteins. The chapters separately examine such issues as mechanisms of metal binding, metal-induced structural changes in proteins, alterations in cellular metal metabolism in disease, and attempts at a therapeutic approach based on protein metal binding.

Get A Copy. The prion protein, PrP C , is a neuronal cell surface glycoprotein. In an abnormal isoform, termed PrP Sc , it is associated with the family of neurodegenerative conditions called prion diseases. PrP C was recently shown to bind copper and there is strong evidence that it has a role in the regulation of brain copper metabolism. Its expression alters copper uptake into cells and enhances copper incorporation into superoxide dismutase enzymes. Also, PrP C has a superoxide dismutase-like function and may, therefore, protect neurons from the onslaught of reactive oxygen species.

This chapter provides an overview of the latest findings in this field and discusses structural and functional aspects of the prion protein. Metallothioneins are ubiquitous low molecular weight proteins characterized by an abundance of the thiol-containing amino acid, cysteine. Metallothionein I and metallothionein II, the most widely expressed isoforms, are co-ordinately regulated in all mammalian tissues, while a third variant, metallothionein III, is predominantly expressed in zinc-containing neurons and absent from non-neural tissue.

Metallothionein proteins have been implicated as regulators of gene expression in homeostatic control of cellular metabolism of metals and in cellular adaptation to stress, including oxidative stress. They regulate transcription, replication, protein synthesis, metabolism, and other zinc-dependent biological processes.

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Because the intracellular concentration of zinc is buffered by complexing with apothionein to form metallothionein, and disordered metallothionein homeostasis results in changes in brain zinc levels, there has been great interest in the potential role of metallothionein regulation in the etiology of neurodegenerative disorders. This chapter commences with a brief discussion of the various brain metallothionein isoforms, followed by a survey of the evidence that metallothioneins are involved in neurodegeneration. Iron-related pathology is present in many neurodegenerative diseases, and the effects of iron mismanagement can serve as either primary or secondary causes of neurodegeneration.

There are many mechanisms by which iron mismanagement can precipitate neurodegeneration, including misregulation of iron import and export, iron deficiency or accumulation, and oxidative damage resulting from loss of iron homeostasis. While the crucial role of iron in neurodegeneration is, in general, beginning to be appreciated, the mechanisms by which loss of iron homeostasis in the brain occurs are still unclear and questions regarding opportunities for therapeutic intervention involving iron chelation remain unanswered.

Parkinson's disease is a common neurodegenerative disorder characterized clinically by motor dysfunction. The primary pathological changes in the Parkinsonian brain are the degeneration of pigmented dopaminergic neurons of the substantia nigra and the development of pathological inclusions called Lewy bodies.

Progressive cell loss in Parkinson's disease is suggested to result from self-sustaining mechanisms related to oxidative mechanisms and mitochondrial dysfunction. A common factor linking oxidative damage, mitochondrial dysfunction, and the development of Lewy bodies in Parkinson's disease is the presence of a significant and pathological increase in the amount of iron in the degenerating substantia nigra.

The role of iron in biochemical pathways proposed to mediate these mechanisms and their association with the etiology of Parkinson's disease is discussed.

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Injections of iron salts into the sensorimotor cortex, hippocampus, and amygdala of experimental animals results in chronic recurrent focal paroxysmal electroencephalographic discharges, behavioral convulsions, and electrical seizures. Some of the above effects of iron can be abrogated by inhibitors of phospholipase A 2 PLA 2 indicating that the damaging effects of iron may be due to perturbation of the lipid environment essential to normal functioning of membrane proteins.

Iron in hemoglobin, or by itself, is also likely to be the cause of human epilepsy, in instances where there is increased iron load in the brain.

These include subarachnoid hemorrhage, intraparenchymal hemorrhages due to head injury and stroke, malaria, human immunodeficiency virus encephalitis, and possibly, neuroleptic drug use. A reduced level of haptoglobin, a hemoglobin-binding protein, has also been observed in select kindred relatives affected with familial idiopathic epilepsy.

An accumulation of iron has been observed in the motor cortex with age, and it is possible that this might contribute to the increased incidence of epilepsy among the elderly. Iron accumulates with time in rat hippocampus after kainate-induced epilepsy.

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The accumulation occurs in oligodendrocytes, and is likely to be a reflection of the high levels of iron in the extracellular space. The accumulation of iron is correlated with increased expression of the divalent metal transporter-1 in astrocytes in the glial scar and increased expression of heme oxygenase-1 in reactive astrocytes and microglia, as well as degenerating neurons at the edge of the scar. The increased divalent metal transporter-1 expression could lead to increased uptake of iron, followed by redistribution to the extracellular space. In this model, iron is the consequence of epilepsy, although it is possible that it can also be a cause of epilepsy.

Further work is necessary to elucidate the effects of lipid peroxidation of the cellular membranes on function of membrane proteins and the role of phospholipases, including PLA 2 , in perturbing the lipid environment. The possible presence of iron in the human brain after epilepsy also needs to be elucidated. The causes of dysregulation of iron in the glial scar after neuronal injury need to be studied. In addition, possible beneficial effects of iron chelators, antioxidants that cross the blood-brain barrier, or neuroprotective gene induction on epilepsy, need to be evaluated.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system caused by a complex interaction between genetic and environmental factors. Support for a role of iron metabolism in multiple sclerosis was obtained by the analysis of the gene encoding the solute carrier family 11 proton-coupled divalent metal ion transporters member 1 SLC11A1 , formerly known as NRAMP1, in the genetically homogenous Afrikaner population of South Africa. Under-representation of allele 2 of the functional Z-DNA forming promoter polymorphism in patients compared with population-matched controls largely excluded the hypothesis that multiple sclerosis is primarily caused by a virus infection, since this allele has previously been linked to various infectious diseases and appears to protect against autoimmune disease.

Manganese is an essential trace element for many living organisms.

Metalloproteins and neuronal death.

It is mostly known as a co-factor for the activity of some important enzymes, like manganese-dependent superoxide dismutase in the mitochondria of neurons and glial cells, and glutamine synthetase in the cytoplasm of astrocytes. The use of electron microscopy imaging and electron energy loss spectroscopy, associated with a transmission microscope, revealed the distribution of manganese in specific cellular structures, emphasizing its localization not only in mitochondria and lysosomes, but also in the nucleus, nucleolus, and likely ribosomes.

The functional role of this distribution is not yet clear. We summarize some studies on the involvement of manganese in nucleic acid functions. In the nucleus, manganese is involved in chromatin and chromosomes' condensation, and can be a physiological stimulating co-factor of DNA and RNA polymerases. Increased manganese concentrations in vitro can induce errors in DNA synthesis. Copper and mercury play a toxic role in several pathological processes, including neurodegeneration. Both ions induced shape changes in erythrocytes, which took the form of echinocytes due to location of the ions in the outer monolayer of the erythrocyte membrane.

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Fluorescence spectroscopy analysis revealed that the interactions occurred in the polar region of me membrane, that is, at the hydrophobic-hydrophilic interface. X-ray experiments indicated that both ions interacted with the polar groups of phospholipids located in the outer monolayer of the erythrocyte membrane. The experimental results confirmed the toxicity of both heavy metals on membrane structure and functions.

The effects of exposure of low lead concentrations on the brainstem and the cerebellum are reviewed. Neurophysiological parameters relative to the neural pathways, auditory function, and vestibular functions were considered. The literature shows that brainstem functions are significantly impaired by lead exposure even at very low levels, and the vestibular system, is one of the most sensitive targets. Multiple actions of lithium are critical to its therapeutic effects.

These complex effects stabilize neuronal activities, support neuronal plasticity, and provide neuroprotection. Three interacting systems appear most critical. Modulation of neurotransmitters by lithium likely readjusts balances between excitatory and inhibitory activities, and so may contribute to neuroprotection. GIF growth inhibitory factor. GSH glutathione.

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IRE iron responsive elements. IRP iron-regulator protein. KNG kininogen.