Many neurodegenerative diseases are characterized by toxic misfolded proteins causing neuronal damage . These noxious proteins display a typical tendency to aggregate and form solid extra- or intracellular deposits as diverse as the plaques of Alzheimer's (AD) and transmissible spongiform encephalopathies (TSEs), the Lewy bodies of Parkinson's disease (PD), the nuclear and cytoplasmic inclusions of Huntington disease (HD), the Bunina bodies of familial amyotrophic lateral sclerosis (ALS), and many others [1-4]. Genes implicated in the various disorders are being progressively identified and cellular and animal models are being developed, supporting the generally accepted belief that mutations in the genes yield abnormal processing of the toxic protein with consequent accumulation and deposition of the misfolded protein. However, gene mutations only account for a few percent of the widely occurring neurodegenerative disorders that are mainly determined by impaired homeostatic control of free radicals and metal ions.
The human brain is estimated to produce more than 1011 free radicals per day : imbalance in prooxidant vs antioxidant homeostasis results in 'oxidative stress' with generation of several potentially toxic reactive oxygen species (ROS). Oxidative stress has been implicated not only in normal brain ageing, but also in many neurodegenerative disorders [5-10]. As a matter of fact, AD, PD, and ALS are all characterized by extensive oxidative damage to cell membranes, proteins, and DNA. ROS are normally implicated in the cell signalling network and are generated by the reaction of oxygen with redox active metal ions through the Fenton reaction. It follows that ROS regulation is tightly linked to the homeostatic control of redox metal ions, namely copper, iron and manganese.
The key factors of AD and TSE are neuronal membrane proteins, the amyloid precursor protein (APP) and the prion protein (PrPc), respectively. The P-amyloid peptide (AP), the major constituent of the deposit in plaques of AD brain, is in fact a 39-43 residues-long fragment of APP. The biological functions of PrPc and APP are not yet well established, but recent findings indicate they are involved in the homeostatic control of copper (see Chapters 4 and 5 of this volume).
PrPc has long been known as a copper-binding protein and recently evidence has been reached about its ability in binding manganese. APP is a transmembrane cell surface glycoprotein accommodating binding sites for either copper or zinc ions. Elucidation of the ways copper interacts with both proteins is likely to provide valuable insight into the role that this redox active metal ion may play in the two neurodegenerative disorders. The chemical aspects of such interactions with PrP, APP, and related proteins and peptides are discussed herein.
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