Iron, in neurodegenerative diseases

An inevitable consequence of ageing is an elevation of brain iron in specific brain regions, e.g. in the putamen, motor cortex, pre-frontal cortex, sensory cortex and thalamus, localized within H- and L-ferritin and neuromelanin with no apparent adverse effect. However, ill-placed excessive amounts of iron in specific brain cellular constituents, such as mitochondria or in specific regions brain, e.g. in the substantia nigra and lateral globus pallidus, will lead to neurodegenerative diseases (Friedreich s ataxia and Parkinson s disease (PD), respectively). We discuss here a few of the examples of the involvement of iron in neurodegenerative diseases. From more on iron metabolism see Crichton, 2001. 

Although iron is essential for normal functioning of the human body, it may aiso play a deleterious role as a trigger of various diseases [ 1,2]. In this chapter, we will present results of studies on the role of iron in neurodegenerative diseases such as Parkinson s disease (PD), Alzheimer s disease (AD), and progressive supranuclear palsy (PSP). We report on studies whose main tool was Mossbauer spectroscopy, but also other complementary techniques such as electron microscopy, enzyme-linked immunosorbent assay (ELISA), and atomic absorption. 

In many crucial biological processes, such as oxygen transport, electron transport, intermediary metabolism, metals play an important part. Therefore, disorders of metal homeostasis, metal bioavailability or toxicity caused by metal excess, are responsible for a large number of human diseases. We have already mentioned disorders of iron metabolism (see Chapter 7) and of copper metabolism (see Chapter 14). The important role, particularly of redox metals such as copper and iron, and also of zinc, in neurodegenerative diseases, such as Parkinson s disease, Alzheimer s disease, etc. has also been discussed (see Chapter 18). We will not further discuss them here. 

Dexter, D.T., Jenner, P., Schapira, A.H.V. and Marsden, C.D. (1992a) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. Ann. Neurol. 32 (Suppl.) 94-100. 

Cole, G. M. Ironic fate can a banned drug control metal heavies in neurodegenerative diseases Neuron 2003,37, 889-890. 

Iron has been implicated in many neurodegenerative diseases, particularly microglia activation and mitochondrial dysfunction. 

In this progressive neurodegenerative disease there is increased deposition of iron within neuromelanin, specifically in the substantia nigra region. Gross cellular... 

Another genetic defect results in failure of hepatic synthesis of ceruloplasmin (aceruloplasminemia), which is a neurodegenerative disease. Retinal damage, secondary iron overload, and insulin-dependent diabetes present in the fourth to fifth decade of life. ... 

Iron deficiency and iron overload are the major disorders of iron metabolism. There are, in addition, many diseases in which abnormal distribution of iron may play primary or secondary roles. Included are such disorders as hyperfer-ritinemia with cataracts, aceruloplasminemia, GRACILE syndrome, neuroferritinopathy, atransferrinemia, and possibly neurodegenerative disease such as Parkinsonism, Hallervorden-Spatz syndrome, and Alzheimer s disease. These latter disorders will not be discussed further here. 

Ceruloplasmin has long been thought to be a ferroxidase and it has been proposed that ceruloplasmin has a custodial role in vivo, ensuring that Fe " " released from cells is oxidised to the potentially less toxic Fe + prior to its incorporation into apotransferrin. Aceruloplasminaemia is a neurodegenerative disease associated with the absence of functional ceruloplasmin due to the presence of inherited mutations within the ceruloplasmin gene. This condition results in disruption of iron homeostasis, with extensive iron accumulation in a number of tissues... 

Rogers, J. T., Randall, J. D., Cahill, C. M., Eder, P. S., Huang, X., Gunshin, H., et al. (2002). An iron-responsive element type II in the 5 -untranslated region of the Alzheimer s amyloid precursor protein transcript. The Journal of Biological Chemistry, 277, 45518—45528. Ross, C. A., Poirier, M. A. (2004). Protein aggregation and neurodegenerative disease. Nature Medicine, 10, SIO—17. 

The first comparison between the iron concentration in SN of parkinsonian patients and the iron concentration in SN from brains of patients who died without clinical or pathological signs of neurodegenerative diseases (control), was... 

---