References

Physiol. Norm. Pathol., 1, 354-367 (1869). 2. Y. J. Li, M. A. Pericak-Vance, J. L. Haines, N. Siddique, D. McKenna-Yasek, W. Y. Hung, P. Sapp, C. I. Allen, W. Chen, B. Hosler, A. M. Saunders, L. M. Dellefave, R. H. Brown, Jr., and T. Siddique, Neurogenetics, 5, 209-213 (2004). 3. L. P. Rowland and N. A. Shneider, N. Engl. J. Med., 344, 1688-1700 (2001). 4. D. W. Mulder, L. T. Kurland, K. P. Offord, and C. M. Beard, Neurology, 36, 511-517 (1986). 5. H. X....

Protein Folding Speed Limit Intrachain Diffusion Dynamics

The formation of tertiary contacts during protein folding is recognized as a pivotal step in the formation of native structure. It is clear that proteins can fold no faster than the rate at which native tertiary contacts are made. The time scales of tertiary contact formation in peptides and proteins have been investigated both experimentally 41,136-143 and theoretically 144-149 . Statistical mechanical models suggest that the probability and rate of forming transient tertiary contacts in...

Binding of Cu2 by Chicken Prion Tandem Repeats

The tandem repeat region of chicken prion consists of hexapeptide units (His-Asn-Pro-Gly-Tyr-Pro, HNPGYP). This region of chicken PrP seems to bind Cu2+ ions as well 18,27,35 . The presence of Pro within the peptide sequence changes the binding ability of chicken hexapeptide repeat when compared to mammalian peptide. The Cu2+ ion binding begins at the His side chain as it was found in mammalian peptides. However, as binding of the Pro amide nitrogen, although likely 38 , is less favorable 39 ,...

The Role Of The Labile Iron Pool In Free Radical Production

The labile iron pool within cells is defined as a pool of redox-active, mostly low molecular weight iron complexes, originally proposed to be a pool of iron in transit between extracellular and intracellular forms of iron. Operationally, it is a pool of chelatable iron, both Fe2+ and Fe3+, associated with a diverse population of ligands such as organic anions (phosphates and carboxylates), polypeptides, and surface components of membranes (e.g., phospholipid head groups) 13 . This means that...

Hallervorden Spatz Syndrome

Hallervorden-Spatz syndrome is an autosomal recessive trait which is relatively uncommon, characterized by progressive Parkinson-like rigidity and mental and emotional retardation 115 . Onset is in late childhood, with death occurring usually within 10 years. It can be considered as a form of iron storage disease, since both the globus pallidus and the substantia nigra have large accumulation of iron mostly in microglia and macrophages, but occasionally in scattered neurons. Many patients with...

Amyloid Precursor Protein And Brain Copper Homeostasis

Recent research has revealed that APP is actively involved in balancing Cu concentrations in cells. In APP and APLP2 knockout mice, increased Cu levels were found in cerebral cortex and liver 7 , whereas overexpression of APP was reported to result in significantly reduced Cu levels in the Tg2576 line 8 . Depending on the conservation of the CuBD, Cu was also found to influence APP processing in cells when Cu greatly reduced the levels of amyloid Ap and caused an increase in the secretion of...

Alzheimers Disease

Alzheimer's disease (AD) (see also Chapter 5) is one of the most common neu-rodegenative maladies in Western societies. Clinical symptoms occur between the ages of 60-70 years. This disease, for which no effective treatment is currently available, initially presents with symptoms of memory loss, after which a progressive decline of both cognitive and motor function occurs. Both genetic and environmental factors are implicated in its development. The amyloidosis which occurs in AD involves...

Elevated Iron and Exacerbation of Excitotoxicity

The striatum has relatively high iron levels, while the hippocampus does not 61 , supporting the possibility that both NMDA (see Section 2.3) and iron need to be elevated for the full neurotoxic effect of HD to manifest. The globus pallidus, on the other hand, is an example of a structure that is less severely affected than the striatum, despite having higher iron concentrations 57 (Figure 2). However, this structure could be less susceptible in adult HD because it has minimal NMDA enervation...

Intensitybased Fluorescent Sensors with Ultraviolet Excitation

Quinolines represent the earliest and most enduring examples of small-molecule fluorogenic agents for Zn2+ in biological environments (Figure 8) 42,46,185 . Zinquin A (R N, 26) Zinquin E (R Et, 27) Zinquin A (R N, 26) Zinquin E (R Et, 27) 29 X N, Y N 30 X NO2, Y N 31 X NO2, Y N02 32 X SO3N, Y N 29 X N, Y N 30 X NO2, Y N 31 X NO2, Y N02 32 X SO3N, Y N Figure S. Quinoline agents for fluorogenic zinc sensing. These sensors are generally based on one of two common platforms, 8-aminoquinoline (8-AQ,...

Neurotoxic Effects in Humans

Although exposure to significant levels of both organic and inorganic forms of mercury can result in neurologic, respiratory, renal, reproductive, immunologic, dermatologic, and a variety of other effects, neurologic effects are the most prominent feature of excessive exposure to metallic and organic mercury in most cases. These include restlessness, memory loss, headaches, anxiety, agitation, irritability, fatigue, confusion, insomnia, mood lability, erythism, irrational behavior, weakness,...

Menkes Disease ATPase ATP7A

The Menkes disease protein has a high degree of homology with Wilson disease ATPase (Figure 4) 33 . The overall identity between these two proteins is 57 . The identity rises to 79 and higher in the phosphatase transduction-phosphorylation and ATP-binding domain. These two proteins have a significant similarity, but there are some significant differences as well, most notably a 78-amino acid insertion between metal-binding domain 1 and 2 in the ATP7A which is not the case in ATP7B. ATP7A is a...

ASynuclein And Parkinsons Disease

Parkinson's disease (PD) is the most common age-related neurodegenerative movement disorder 215 . The primary symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra region of the brain stem 216 . A diagnostic hallmark of PD is the presence in the cerebral cortex of intracellular inclusions (Lewy bodies and neurites) 217,218 , but the role of these proteina-cious materials in the pathogenic process has not been established. a-Synuclein (a-syn), an abundant...

Specific Toxicity of Myelinated Projection Neurons

Images Neurotoxicity

At very early and even presymptomatic stages of HD there is evidence for myelin breakdown and loss (see Figure 1 top 6 and 7,9,10,13-17 ) (see also Figure 3 in Section 3.1.1). The spreading pattern of myelin breakdown seems to follow the spreading pattern of neurotoxic damage described above. Earlier-myelinating axons such as those in the occipital system show more evidence of myelin breakdown than later-myelinating axons in frontal regions 17 and this same spreading pattern is also noted in...

Menkes Disease

Menkes disease was first characterized by John Menkes and co-workers in 1962 during the course of a study of five patients from the same family who died before the age of three 20 . In their original study they noticed that the disease seemed to be confined to males and was inherited in a sex-linked recessive manner. The disease is caused by an impairment in the absorption of dietary copper and severe disturbance in the intracellular transport of copper 21 . Menkes disease patients are not able...

Oligodendrocytes as the Iron Storage Cell in Development

Oligodendrocytes have the highest iron content of all brain cell types 63-66 . These cells are unique in their capacity to obtain their iron directly through binding the iron storage protein ferritin 67 , and may be directly involved in brain iron regulation 68 . In HD, oligodendrocyte production is upregulated and results in increased density of these cells before any clinical symptoms appear 5 . During development, brain ferritin binding coincides with the onset and progression of myelination...

Absorption from the Gastrointestinal Tract

The mechanisms by which iron crosses the membrane of the enterocyte and is then transferred to the circulation have become much more clearly understood in the last few years. A number of new proteins have been identified which are involved in mucosal iron absorption (Figure 2). Heme iron is the most effective source of dietary iron in man, and after its uptake across the apical (brush-border) membrane of the intestine, probably via a specific receptor, its iron is released by the action of heme...

Unfolded Cytochrome c

FET kinetics measurements have been employed to characterize the conformational heterogeneity in unfolded yeast cyt c 49,50 . Six different Cys variants were engineered by site-directed mutagenesis 50 and labeled with the thiol-reactive fluorophore acid (AEDANS) (Figure 8, inset). FET kinetics were measured in each of the six DA proteins (K4C, H39C, D50C, E66C, L85C, K99C) (Figure 8) with AEDANS and heme (ro 39 A) serving as the fluorescent donor and energy acceptor, respectively 49,50 . The...

Neuromelanin and Iron

Histochemical studies ascribe the localization of iron in the SN primarily to the glial compartment and changes in glia-associated ferritin have been described in PD. While some iron sequestration appears to occur in a-synuclein in Lewy bodies, the importance of this iron for neurodegeneration is unknown. A more important source of intraneuronal iron involved in the oxidative pathway is neuromelanin, which characterizes the dopaminergic neurons in the human SN. Neuromelanin occurs as granules,...

Menkes Disease Gene

The Menkes disease gene (ATP7A) was isolated and identified independently by three groups using positional cloning 31-33 . The gene has 23 exons and spans a genomic region of approximately 150kb 34,35 . After the exon coding for the fifth metal-binding domain (exon five in ATP7A and exon 3 in ATP7B), the coding region for both the Wilson disease gene (ATP7B) and Menkes disease gene (ATP7A) are virtually identical. Approximately 20 of the mutations in the Menkes disease are insertion deletion...

Neuromelanin and Proteins

In addition to binding metals, neuromelanin also contains and interacts with proteins. Recent studies of neuromelanin using 13C-NMR demonstrated that the spectral pattern of neuromelanin isolated from PD brain exhibits a comparatively decreased melanin signal than that from control neuromelanin. This appeared to be due to the presence of a novel protease-resistant, lipoproteinic material not seen in the healthy brain 99 . Recent work has further shown that a-synuclein, one of the major...

Aceruloplasminemia

As was pointed out earlier, ceruloplasmin is thought to play an important role as a ferroxidase, in the incorporation of iron into apotransferrin. The role of ceruloplasmin in iron metabolism was established unequivocally with the identification of aceruloplasminemia 124,125 . Ceruloplasmin is a member of the multicopper oxidase family of enzymes, mostly synthesized in liver, the major source of serum ceruloplasmin, but also in other tissues, including brain. Within the CNS, ceruloplasmin is...

Sources Of Increased Iron In Parkinsons Disease

The question then arises as to the source of the increased iron. There are several possibilities and iron misregulation in the brain may have genetic (see Section 2.2) and nongenetic causes ( 52 and references cited therein). Firstly, local alterations in the BBB might result in an increased entry of peripheral iron for example, a change in the normal iron regulatory systems, such as a local increase in transferrin receptor number could result in an increase in SN iron. Results from studies...

Contributors

Numbers in parentheses indicate the pages on which the authors' contributions begin. Henry G. Abadin Agency for Toxic Substances and Disease Registry (ATSDR), US Department of Health and Human Services, Division of Toxicology, Mailstop E-29, 1600 Clifton Road, Atlanta, GA 30333, USA (395) George Bartzokis (1) Department of Neurology, Alzheimer's Disease Center, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA, < gbar ucla.edu> , (2) Laboratory...

Parallels Between the Spread of Myelination and Huntingtons Disease Neurotoxicity

The normal lifelong trajectory of human brain myelination has a quadratic-like (inverted U) shape with increasing myelin content that peaks in middle-age and subsequently breaks down and declines in older age (reviewed in 25,28,36 ). The myelin-centered view of the human brain defines our entire lifespan and especially the first six decades as a period of development as myelinated white matter volume increases 29,37 . At birth oligodendrocytes each myelinate single axon segments in the motor...

Specific Examples

The only disease that has been unambiguously related directly to metal ions (iron) and catecholamines is Parkinson's disease and so this chapter deals almost exclusively with this condition. However, for the sake of completeness we will now describe the important clinical features of this and several related neurode-generative diseases. Table 1. Classification of neurodegenerative diseases according to molecular biological criteria. Alzheimer's ApoE e 4 19 disease sporadic Alzheimer's disease...

Neurodegenerative Diseases and Metal Ions

Over the years substantial evidence has accumulated implicating that metal ions play a role in the pathophysiology and pathogenesis of neurodegenerative disorders. This is emphasized in Chapter 1, which sets the scene for this volume and provides an organizational frame for metal-related disorders, namely (i) those caused by a defect in metal ion transport or homeostasis (ii) those caused by toxicological exposure to metals and (iii) those caused or associated with metalloprotein aggregation...

Toxicokinetics and Mechanism of Action 411 Toxicokinetics

The extent of absorption, the residence time in the body before metabolism, and the nature and degree of neurotoxicity are all dependent upon the specific species of mercury. In the case of metallic (liquid, elemental) mercury, only the inhalation route has proven to be biologically relevant in most instances. Less than 0.01 is typically absorbed through the gastrointestinal (GI) tract 146 compared with up to 80 of inhaled mercury vapor 147,148 . Gastrointestinal absorption of mercury varies...

Iron Homeostasis

It has been known for a long time that ferritin biosynthesis can be regulated in response to changes in cellular iron content even when transcription has been inhibited 17 , and it was subsequently shown that this involves a stem loop of approximately 30 nucleotides in the 5' untranslated region of the ferritin mRNA. This sequence is highly conserved in all ferritin mRNAs. Biosynthesis of the transferrin receptor is also regulated at the level of translation, but in this case the regulation...

Triplet Length and Age at Onset

In AD and PD age-related brain iron increases act as a risk factor that impacts age at onset of the disease with earlier age at onset being associated with increased iron levels (reviewed in 110 ). A similar interaction between age-related increases in striatal iron levels and age at onset may occur in HD with huntingtin polyglutamine length acting to influence this interaction. In adult-onset HD it is well-established that in general less severely affected individuals have a lower...

IronIII and Catecholamines

The simple aqua-cations of iron(III) are highly insoluble at physiological pHs and iron(II) is unstable with respect to oxidation to iron(III) and therefore, any iron present in biological systems must be complexed before it can be transported and utilized. Solubilization is maintained by the presence of a pool of low molecular weight complexes lying between where the iron is stored and where it is to be employed. Little is known about the chelators involved, but in mammals citrate seems a...

Experimental Approaches To Brain Iron Loading

The neurotoxins (MPTP) and 6-hydroxydopamine (6-OHDA), induce many of the pathological changes that occur in PD and are widely used as animal models of this disease. MPTP induces nigral degeneration in several species including rat, mouse, dog, cat, and monkey (reviewed in 151 ). Essentially, MPTP will cross the BBB to be converted by monoamine oxidase B in glial cells to the active form, 1-methyl-4-phenylpyridinium (MPP+) (Figure 23). MPP+ will accumulate in dopaminergic cells prior to its...

Brain Iron in Parkinsons Disease

Increased regional total brain iron has been identified in a variety of neurodegenerative disorders such as PD, movement disorders associated with parkinsonism, Huntington's disease and the dementia syndromes, including AD 5,7,28 . The most striking feature of these changes is that increased brain iron is confined to those brain regions most affected by the degeneration characteristic of the particular disorder for example, in the movement disorders total iron levels are increased in the basal...

Linear Amyloidlike Filamentous Arrays

Structures of the metal deficient SOD1 MBR mutants S134N and H46R reveal novel interactions between SOD1 dimers 82 (Figure 5). The -barrel elements of these protein structures do not differ from wild-type SOD1. However, the electrostatic and zinc loop elements are disordered such that some of the residues of these loops were unable to be modeled. The S134N substitution occurs in the electrostatic loop (Figure 4, right subunit), and has both copper sites occupied, but one zinc site empty per...

Neurotoxicity of Cadmium Lead and Mercury

Abadin, and John F. Risher Agency for Toxic Substances and Disease Registry (ATSDR), US Department of Health and Human Services, Division of Toxicology, Mailstop F-32, 1600 Clifton Road, Atlanta, GA 30333, USA < hpoh1 cdc.gov> 2.1 Toxicokinetics and Mechanism of Action 397 2.1.2 Mechanism of Action 398 2.2 Neurotoxicity Studies in Humans 399 2.3 Neurotoxicity Studies in Animals 400 3.1 Toxicokinetics and Mechanism of Action 400 3.1.2 Mechanism of Action 401 3.2...

In Vivo Assessment of Iron in Huntingtons Disease and Other Age Related Neurodegenerative Brain Diseases

Lu,13 Todd A. Tishler,13 5 and Susan Perlman1 1 Department of Neurology, Alzheimer's Disease Center, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA < gbar ucla.edu> 2Laboratory of Neuroimaging, Department of Neurology, Division of Brain Mapping, UCLA, Los Angeles, CA 90095, USA 3Greater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, CA 90073, USA 4Department of Psychiatry, Charles R....

Metal Ions and SOD1 Structure

First characterized in 1969 83 , SOD1 is a homodimeric molecule characterized by an eight-stranded Greek key -barrel fold in each subunit 84 . The two polypeptides are related by a two-fold axis of rotation at the dimeric interface (Figure 1A), which buries approximately 660 A2 of solvent accessible surface area per polypeptide and is formed by a series of reciprocal hydrogen bonding, hydrophobic, and water-mediated interactions 81 . The wild-type SOD1 holoenzyme is unusually stable, retaining...

Brain Iron as a Function of

The iron content of some parts of the brain is very high - significantly greater iron concentrations, as high as 150-200 g g protein, are found in the substantia nigra and the globus palidus than in liver 37 , and other brain regions with high concentrations are the dentate gyrus, interpeduncular nucleus, thalamus, ventral pallidus, nucleus basilis and red nucleus (Figure 9). There is a consensus that iron accumulates in the brain as a function of age. However, this process is quite specific...

Storage and Intracellular Utilization

Most of the iron delivered to or acquired by cells is believed to cross the cell membrane in ferrous form and to enter a poorly characterized intracellular Figure 3. The transferrin cycle. Holotransferrin (HOLO-TF) binds to transferrin receptors (TFR) at the cell surface. The complexes localize to clathrin-coated pits, which invaginate to initiate endocytosis. Specialized endosomes form, and are acidified by a proton pump. At the acidic pH, iron is released from transferrin and is...

Cu2 Ion Binding to the Mammalian Prion Protein Octapeptide Repeat Fragment

The binding of Cu2+ ions to the -PHGGGWGQ- fragment (N-terminus protected) critically depends on the imidazole moiety of the His residue, which acts as an anchoring site. Around physiological pH the octapeptide involves three nitrogen atom donors, an imidazole and two amide donors from two adjacent glycine residues 22-28 . The interesting feature in the Cu2+ interactions with the mammalian octarepeat fragment is the close proximity of the Trp side chain to the metal ion in solution (Figure 2a)...

The Chemical Interplay between Catecholamines and Metal Ions in Neurological Diseases

Jameson,1 Reginald F. Jameson,2 and 'Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9 163-AC, A-1060 Vienna, Austria 2Emeritus Professor, University of Dundee, Scotland, UK lt rjdundee aol.com gt 3Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria lt kurt.jellinger univie.ac.at gt 1 GENERAL INTRODUCTION 282 2 NEURODEGENERATIVE DISEASES 283 2.1 General Description 283 2.2.1 Parkinson's Disease 289 2.2.2...

Toxicokinetics and Mechanism of Action

Once deposited in the lower respiratory tract, particulate lead is almost completely absorbed, and all chemical forms of lead seem to be absorbed 45,46 . The extent and rate of gastrointestinal absorption are influenced by physiological states of the exposed individual e.g., age, fasting, nutritional calcium and iron status and physicochemical characteristics of the medium ingested e.g., particle size, mineralogy, solubility, lead species . Gastrointestinal absorption appears to be higher in...

Transport Trafficking and Homeostasis

The high concentrations and complex storage patterns of Zn2 in neuronal tissue demand that the brain maintains strict control over its cellular Zn2 homeosta-sis. The concentration of Zn2 in the extracellular cerebrospinal fluid CSF 0.15 M 46 is two orders of magnitude less than in blood 11-23 M 60 , and the uptake of Zn2 across the blood-brain barrier BBB is homeostatically controlled. The entry of Zn2 into neurons appears to overlap with routes of Ca2 entry, and at least four specific pathways...

Wilson Disease ATPase ATP7B 411 Structural Studies of ATP7B

Transmembrane Regions

The Wilson disease gene is predicted to encode a copper transporting P-type ATPase having many features common to cation-transporting P-type ATPases Figure 2 . There are six metal-binding motifs, GMTCXXC at the N-terminus, the TGEA motif actuator domain , the CPC motif in the sixth transmembrane, the DKTGT and TGDN motifs phosphorylation domain and SEHPL, a conserved motif found in all heavy-metal transporting ATPases. A complete structural description of ATP7B remains unsolved. However,...

Fluorescent Sensors for Ratiometric Detection of Zinc

Fluorescent probes that report ionic Zn2 in aqueous media by an increase in emission intensity are of considerable practical utility for interrogating its met-alloneurochemistry. These intensity-based sensors are not ideal for applications that require quantitative measurements of changes in intracellular or extracellular Zn2 , however, because of variations in sample thickness, excitation intensity, emission collection efficiency, and artifacts associated with probe concentration and...

Intensitybased Fluorescent Sensors with Visible Excitation Including Xanthenones

Fluorescent sensors that operate with visible excitation and emission wavelengths hold distinct advantages over their counterparts with shorter ultraviolet profiles. Excitation in the ultraviolet region can damage biological samples and trigger native cellular autofluorescence, particularly from nicotinamide adenine dinucleotide NADH . The rising use of laser excitation sources for fluorescence microscopy has also increased the demand for chromophores with optical profiles in the visible...