Neurodegenerative diseases and metal ions

Volume 1, devoted solely to the vital research area concerning the role of metal ions in neurodegenerative diseases, offers in 15 stimulating chapters an authoritative and timely view of this fascinating subject. Written by 41 internationally recognized experts, Neurodegenerative Diseases and Metal Ions highlights, supported by 130 illustrations, the recent progress made in understanding the role metal ions play in diseases like transmissible spongiform encephalopathies (Creutzfeldt-Jakob and related diseases), Alzheimer's, Parkinson's, Huntington's, Wilson's and Menkes' diseases, as well as in familial amyotrophic lateral sclerosis and others. The interplay between metal ions, catecholamines and the formation of reactive oxygen species resulting in oxidative stress is considered, as is the metalloneurochemistry of zinc and the neurotoxicity of aluminum, cadmium, lead, and mercury. The need for novel drugs which manipulate metal-centered neuropathology is emphasized. With more than 2000 references to assist further research, Neurodegenerative Diseases and Metal Ions is an essential resource for scientists and students in many disciplines, including biological inorganic chemistry, molecular biology, enzymology, pharmacology, physiology, medicine, and toxicology. 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 and/or misfolding. Indeed, misfolded proteins are implicated in a rapidly growing list of debilitating illnesses like Alzheimer's, Parkinson's, and Creutzfeldt-Jakob diseases. Therefore Chapter 2 deals with protein folding and misfolding; structures, energetics, and dynamics of transient species are considered in detail because their character­ization is an essential step in understanding the benign and malignant pathways of protein folding. The three chapters following these general considerations are devoted to metal ion interactions, mainly of copper, with mammalian prion proteins and their fragments, to transmissible spongiform encephalopathies (Creutzfeldt-Jakob and related diseases) as well as to the amyloid precursor protein (Alzheimer's disease). Chapters 6 and 7 consider in particular the role of iron in Parkinson's and Huntington's diseases, respectively, whereas Chapter 8 details the interrelation between copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis. The malfunc­tioning of copper transport in Wilson and Menkes diseases, where copper accumulates or is not absorbed, respectively, is dealt with in Chapter 9. The special role of iron in neurodegenerative diseases and the chemical interplay between catecholamines and metal ions are in the focus of Chapters 10 and 11, respectively; in this context Parkinson's, Alzheimer's and Huntington's diseases are considered again, but from a different view, in addition to neurodegeneration with brain iron accumulation (formerly Hallervorden-Spatz syndrome), neuroferritinopathy, aceruloplasminemia, Friedreich's ataxia, and taupathies. The disruption of the homeostasis of metal ions can have devastating effects as is evident throughout the book. This also holds for the essential zinc; its metalloneurochemistry, i.e., its physiology and pathology as well as probes and sensors to detect it are covered extensively in Chapter 12. Next to metal ions like manganese, iron, copper, and zinc, which are essential but may also be toxic due to the creation of reactive oxygen species resulting in oxidative stress, there are other metal ions which are a priori neurotoxic. Among these is aluminum, and its role in neurodegenerative processes is reviewed in Chapter 13. Cadmium, lead, and mercury are important from the viewpoint of public health because they are released into the environment by human activities; their neurotoxicity is covered in Chapter 14. The terminating Chapter 15 summarizes in a general way the medicinal chemistry of metal-centered brain diseases and indicates other neurological disorders that may involve metal ions like polyneuropathy, multiple sclerosis, macular degeneration, progressive supranuclear palsy or the restless leg syndrome which are not otherwise covered in the book because knowledge is scarce. It is clear that there is an urgent need for developing novel drugs and classes of drugs that manipulate metal-centered neuropathology more precisely and elegantly than the presently (only partly) available chelation therapies. It is hoped that this volume stimulates research into this direction.