Altered Brain Metabolism of Iron as a Cause of Neurodegenerative Diseases?

: Iron is the most abundant metal in the human body (Pollitt and Leibel, 1982; Youdim, 1988), and the brain, like the liver, contains a substantially higher concentration of iron than of any other metal (Yehuda and Youdim, 1988). Within the brain, iron shows an uneven distribution, with high levels in the basal ganglia (substantia nigra, putamen, caudate nucleus, and globus pallidus), red nucleus, and dentate nucleus (Spatz, 1922; Hallgren and Sourander, 1958; Hill and Switzer, 1984; Riederer et al., 1989). Iron deposition in the brain is mainly in organic storage forms such as ferritin but not hemosiderin (Hallgren and Sourander, 1958; Octave et al., 1983), with relatively little in a free and reactive form. Although the function of a regionally high brain iron content is unknown, the homeostasis of brain iron is thought to be necessary for normal brain function, especially in learning and memory (Youdim et al., 1989; Yehuda and Youdim, 1989; Pollit and Metallinos‐Katsaras, 1990; Youdim, 1990). Thus, a high content of brain iron may be essential, particularly during development, but its presence means that injury to brain cells may release iron ions that can lead to oxidative stress via formation of oxygen free radicals. Such radicals are thought to be involved in lipid peroxidation of the cell membrane, leading to increased membrane fluidity, disturbance of calcium homeostasis, and finally cell death (Youdim et al., 1989; Halliwell, 1992). Iron is an essential participant in many metabolic processes, including (a) DNA, RNA, and protein synthesis, (b) as a cofactor of many heme and nonheme enzymes, (c) the formation of myelin, and (d) the development of the neuronal dendritric tree (Ben‐Shachar et al., 1986; Youdim et al., 1991b). A deficiency of iron metabolism would therefore be expected to alter some or all of these processes (Jacobs and Worwood, 1980; Youdim, 1985, 1988). Studies of iron distribution in the human brain have demonstrated that the degree of iron deposition, primarily in the basal ganglia (a predominantly dopamine structure), increases with age (Hallgren and Sourander, 1958) and in certain disorders, most notably the basal ganglia disorders (Seitelberger, 1964). This review will present some of the experimental evidence indicating a role of disturbed iron metabolism as a cause of the neurodegenerative disorder Parkinson's disease and possibly other neurodegenerative disorders such as Alzheimer's disease. In addition, some of the neuroche