Metals and Neurodegeneration

Metals and Neurodegeneration
Chapter 21 Metals and Neurodegeneration Copyright © 2012 Elsevier Inc. All rights reserved.

Copyright © 2012 Elsevier Inc. All rights reserved.
FIGURE 21.1 Estimated rates of occurrence of Alzheimer’s disease in the general population in Western societies. (Source WHO regional Office for southeast Asia.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE 21.2 Characteristic neurodegenerative disease neuropathological lesions involve deposition of abnormal proteins. (From Ross & Poirier, Copyright 2004 with permission from Nature Publishing Group.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE 21.3 Origins and consequences of oxidative stress in disease. Reactive oxygen species (ROS) are constantly generated inside cells by oxidase enzymes and by dismutation of the superoxide anion, and their intended functions range from host defence to signal transduction. There are several cellular systems that eliminate ROS, however, endogenous and exogenous triggers can cause the overproduction of ROS or the impairment of antioxidant defence systems, leading to a deleterious condition known as ‘oxidative stress’. Adaptive upregulation of defence systems can protect against damage, either completely or partially, but oxidative-stress-mediated damage to all types of biological macromolecules often leads to tissue injury, and eventually to cell death by necrosis or apoptosis. (From Dalle-Donne, Giustarini, Colombo, Rossi, & Milzani, Copyright 2003 with permission from Elsevier.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE 21.4 Schematic diagram of reactive hydroxy-alkenals generated during lipid peroxidation of n-3 and n-6 polyunsaturated fatty acids. (From Catala, Copyright 2009 with permission from Elsevier.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE 21.5 The production of protein carbonyls. (a) This can arise from direct oxidation of amino-acid side chains (Pro, Arg, Lys, and Thr). (b) Protein carbonyl derivatives can also be generated through oxidative cleavage of proteins, via the -amidation pathway or through oxidation of glutamine side chains, leading to the formation of a peptide in which the N-terminal amino acid is blocked by an -ketoacyl derivative. (c) The introduction of carbonyl groups into proteins can occur by Michael addition reactions of ,-unsaturated aldehydes, such as 4-hydroxy-2-nonenal, malondialdehyde and 2-propenal (acrolein), derived from lipid peroxidation, with either the amino group of lysine, the imidazole moiety of histidine, or the sulfydryl group of cysteine. (d) Carbonyl groups can also be introduced into proteins by addition of reactive carbonyl derivatives by the reaction of reducing sugars or their oxidation products, with the amino group of lysine residues. (From Dalle-Donne et al., Copyright 2003 with permission from Elsevier.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE 21.7 A putative model of the role of three proteins linked with Parkinson’s disease (PD). In healthy neurons, the cytoplasmic concentration of -synuclein (blue) is tightly controlled. Glycosylation (green) of -synuclein is required for its ubiquitination (Ub) (yellow circles), probably by parkin. Proteasomal degradation of ubiquinylated -synuclein produces peptideeubiquitin conjugates, and subsequent recycling of ubiquitin might be controlled by ubiquitin C-terminal hydrolase L1 (UCH-L1). An increase in cytoplasmic -synuclein concentration, as a result of increased synthesis or via inactivation of parkin, can promote its aggregation. If the gene encoding -synuclein is mutated, the increased concentration can promote oligomerisation of -synuclein, which is eventually converted to Lewy bodies, the pathological hallmark of PD brains. (From Barzilia & Melamed, Copyright 2003 with permission from Elsevier.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE 21.8 Furin activity and the fate of AbPP cleavage by - and -secretases. Low cellular iron levels are thought to increase furin activity, stimulating the nonamyloidogenic pathway. In contrast, high cellular iron levels decrease furin activity and may activate the amyloidogenic pathway. (From Altamura & Muckenthaler, Copyright 2009 with permission from IOS Press.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE 21.9 Models of zinc and copper in the glutamatergic synapse in health and in Alzheimer’s disease (a) the healthy synapse (b) Alzheimer’s disease synapse. (From Duce & Bush Copyright 2010 with permission from Elsevier.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE Frataxin mutations. The commonest mutation is the GAA expansion in the first intron of the frataxin gene (98%). Boxes represent exons and blue bars introns of the frataxin gene. Asterisks indicate the number of families reported with each mutation. (From Dürr, Copyright 2002 with permission from Elsevier.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE Different ALS-associated mutations of SOD1 can increase aggregation of the SOD1 polypeptide for fundamentally distinct reasons. (From Shaw & Valentine, Copyright 2007 with permission from Elsevier.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE Schematic representation of the physiological role of prion protein (PrPc) in copper homeostasis and redox signalling. (From Crichton & Ward, 2006.) Copyright © 2012 Elsevier Inc. All rights reserved.

FIGURE Proteins involved in copper uptake, incorporation into ceruloplasmin and biliary excretion in normal and Wilson’s disease hepatocytes. (From Crichton & Ward, 2006.) Copyright © 2012 Elsevier Inc. All rights reserved.

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