The Role of Iron and Copper in the Aetiology of Neurodegenerative Disorders
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CNS Drugs 2002; 16 (5): 339-352 1172-7047/02/0005-0339/$25.00/0 © Adis International Limited. All rights reserved.
The Role of Iron and Copper in the Aetiology of Neurodegenerative Disorders Therapeutic Implications George Perry, Lawrence M. Sayre, Craig S. Atwood, Rudolph J. Castellani, Adam D. Cash, Catherine A. Rottkamp and Mark A. Smith Institute of Pathology, Case Western Reserve University, Ohio, Cleveland, USA
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . 1. Free Radical Production . . . . . . . . . . . . . . . 2. Metal Imbalance in Neurodegenerative Disease 3. Metalloenzyme Dysfunction . . . . . . . . . . . . 4. Amyotrophic Lateral Sclerosis . . . . . . . . . . . 5. Prion Disease . . . . . . . . . . . . . . . . . . . . . 6. Parkinson’s Disease . . . . . . . . . . . . . . . . . . 7. Alzheimer’s Disease . . . . . . . . . . . . . . . . . 8. Conclusions and Therapeutic Potential . . . . . .
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Abnormalities in the metabolism of the transition metals iron and copper have been demonstrated to play a crucial role in the pathogenesis of various neurodegenerative diseases. Metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases is reviewed in this article in depth. While there is documented evidence for alterations in the homeostasis, redox-activity and localisation of transition metals, it is also important to realise that alterations in specific copper- and iron-containing metalloenzymes appear to play a crucial role in the neurodegenerative process. These changes provide the opportunity to identify pathways where modification of the disease process can occur, potentially offering opportunities for clinical intervention. As understanding of disease aetiology evolves, so do the tools with which diseases are treated. In this article, we examine not only the possible mechanism of disease but also how pharmaceuticals may intervene, from direct and indirect antioxidant therapy to strategies involving gene therapy.
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Interest in the roles of copper, iron and other trace redox-active transition metals has grown exponentially in recent years as their critical role in the pathogenesis of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and prion diseases has been elucidated. While these transition metals are essential in many biological reactions, alterations in their homeostasis, redoxactivity and/or sequestration can have profound cellular consequences, including
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