title: Biological metals and metal-targeting compounds in major neurodegenerative diseases.
abstract: Multiple abnormalities occur in the homeostasis of essential endogenous brain biometals in age-related neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. As a result, metals both accumulate in microscopic proteinopathies, and can be deficient in cells or cellular compartments. Therefore, bulk measurement of metal content in brain tissue samples reveal only the "tip of the iceberg", with most of the important changes occurring on a microscopic and biochemical level. Each of the major proteins implicated in these disorders interacts with biological transition metals. Tau and the amyloid protein precursor have important roles in normal neuronal iron homeostasis. Changes in metal distribution, cellular deficiencies, or sequestration in proteinopathies all present abnormalities that can be corrected in animal models by small molecules. These biochemical targets are more complex than the simple excess of metals that are targeted by chelators. In this review we illustrate some of the richness in the science that has developed in the study of metals in neurodegeneration, and explore its novel pharmacology.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, 3010, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008670:Metals / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D056831:Coordination Complexes; D008670:Metals