Copper in disorders with neurological symptoms: Alzheimer's, Menkes, and Wilson diseases

Copper is an essential element for the activity of a number of physiologica lly important enzymes. Enzyme-related malfunctions may contribute to severe neurological symptoms and neurological diseases: copper is a component of cytochrome c oxidase, which catalyzes the reduction of oxygen to water, the essential step in cellular respiration. Copper is a cofactor of Cu/Zn-supe roxide-dismutase which plays a key role in the cellular response to oxidati ve stress by scavenging reactive oxygen species. Furthermore, copper is a c onstituent of dopamine-p-hydroxylase, a critical enzyme in the catecholamin e biosynthetic pathway. A detailed exploration of the biological importance and functional properties of proteins associated with neurological symptom s will have an important impact on understanding disease mechanisms and may accelerate development and testing of new therapeutic approaches. Copper b inding proteins play important roles in the establishment and maintenance o f metal-ion homeostasis, in deficiency disorders with neurological symptoms (Menkes disease, Wilson disease) and in neurodegenerative diseases (Alzhei mer's disease). The Menkes and Wilson proteins have been characterized as c opper transporters and the amyloid precursor protein (APP) of Alzheimer's d isease has been proposed to work as a Cu(II) and/or Zn(II) transporter. Exp erimental, clinical and epidemiological observations in neurodegenerative d isorders like Alzheimer's disease and in the genetically inherited copper-d ependent disorders Menkes and Wilson disease are summarized. This could pro vide a rationale for a link between severely dysregulated metal-ion homeost asis and the selective neuronal pathology. (C) 2001 Elsevier Science Inc.