NM protein, reduce the iron-binding capacity, and release sequestered iron in cytoplasm. These events finally induce the selective cell death of NM-containing neurons in the SNpc and the accumulation of Lewy bodies, the major pathological characteristics of PD.
See also: Alpha-synuclein; Complex I Deficiency; Dopamine; Mitochondrial Dysfunction; PARK1, Alpha Synuclein; Parkinson’s Disease: Definition, Diagnosis, and Management; Proteasome Function in Movement Disorders; Substantia Nigra.

Further Reading
Ben-Shachar D, Riederer P, and Youdim MB (1991) Iron–melanin interaction and lipid peroxidation: Implications for Parkinson’s disease. Journal of Neurochemistry 57: 1609–1614. Bush WD, Garguilo J, Zucca FA, et al. (2006) The surface oxidation potential of human neuromelanin reveals a spherical architecture with a pheomelanin core and a eumelanin surface. Proceeding of the National Academy of Sciences of United State of America 13: 14785–14789. Double KL, Dedov VN, Fedoroq H, et al. (2008) The comparative biology of neuromelanin and lipofuscin in the human brain. Cell and Molecular Life Sciences 65: 1669–1682. Fasano M, Bergamosco B, and Lopino L (2006) Modifications of the iron-neuromelanin system in Parkinson’s disease. Journal of Neurochemistry 96: 909–916. Fedorow H, Halliday GM, Rickert CH, et al. (2006) Evidence for specific phases in the development of human neuromelanin. Neurobiology of Aging 27: 506–512.

Fedorow H, Tribl F, Halliday G, Gerlach M, Riederer P, and Double KL (2005) Neuromelanin in human dopamine neurons: Comparison with peripheral melanins and relevance to Parkinson’s disease. Progress in Neurobiology 75: 109–124. Halliday GM, Ophof A, Broe M, et al. (2005) a-Synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson’s disease. Brain 128: 2654–2664. Naoi M, Maruyama W, Yi H, et al. (2008) Neuromelanin selectively induces apoptosis in dopaminergic SH-SY5Y cells by deglutathionylation in mitochondria: Involvement of the protein and melanin component. Journal of Neurochemistry 105: 2489–2500. Riederer P, Reichmann H, Youdim MBH, and Gerlach M (eds.) (2006) Parkinson’s Disease and Related Disorders. Journal of Neural Transmission (supplement 70), p. 506. Wien/New York: Springer. Sasaki M, Shibata E, Tohyama K, et al. (2006) Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson’s disease. NeuroReport 17: 1215–1218. Shamoto-Nagai M, Maruyama W, Yi H, et al. (2004) Neuromelanin inhibits enzymatic activity of 26S proteasome in human dopaminergic SH-SY5Y cells. Journal of Neural Transmission 111: 1253–1265. Shamoto-Nagai M, Maruyama W, Yi H, et al. (2006) Neuromelanin increases oxidative stress in mitochondria through release of iron: Mechanism behind the inhibition of 26S proteasomes. Journal of Neural Transmission 113: 633–644. Tribl F, Gerlach M, Marcus K, et al. (2005) ‘Subcellular proteomics’ of neuromelanin granules isolated from the human brain. Molecular and Cellular Proteomics 4.7: 945–957. Zecca L, Youdim MBH, Riederer P, Connor JR, and Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nature Reviews Neuroscience 5: 863–873. Zucca FA, Giaveri G, Gallorini M, et al. (2004) The neuromelanin of human substantia nigra: Physiological and pathological aspects. Pigment Cell Research 17: 610–617.

C G Goetz, Rush University Medical Center, Chicago, IL, USA
ã 2010 Elsevier Ltd. All rights reserved.

Mercury – An element that in organic and inorganic forms can be toxic to the nervous system. Neurasthenia – A neurological condition marked most prominently by fatigue and lassitude. Many other symptoms may accompany these feelings including headache and other, often vaguely localized pains. Tremor – A to-and-fro movement around a joint.

Mercury Compounds and the Nervous System
Human mercurial intoxication results from exposure to the metal, to its inorganic salts, to organic

mercury-containing compounds that are degraded to the inorganic metal. Another form of mercurialism, with different chemical and clinical manifestations, results from intoxication with alkyl compounds, particularly methyl and ethyl mercury. Inorganic mercury poisoning occurs as an industrial disease during paper manufacture, in the preparation of chlorine, and as a result of exposure to certain other chemical processes. Historically, mercurialism was associated with the hat manufacturing industry, because mercuric nitrate was used for processing felt. Acute poisoning has also followed the use of mercuric chloride as a local antiseptic, the excessive use of calomel as a diuretic, and following merthiolate ear irrigations. Dental amalgams release small amounts of mercury, available data do not indicate that this exposure represents a significant clinical risk of neurological intoxication. The chief atmospheric source of mercury pollution is through the burning of coal and other fossil fuels. Metallic

inorganic mercury levels may account for 82–100% of brain mercury after organic mercury exposure if the autopsy is done several years after exposure. often termed historically as mercurial neurasthenia. Personality changes that can accompany or precede the motor phenomena include fatigue. weakness in the lower limbs. as a result. and locomotor hyperactivity when weakness does not occur. Muscle cramps and convulsions may develop. Toxic Mechanisms Serum concentrations are unreliable indicators of inorganic mercury toxicity. Elemental. Specifically. however. Organic mercury readily enters the brain from the blood. depending on chemical form. as typified in Lewis Carroll’s Mad Hatter. excretion rates are extremely low since inorganic mercury cannot leave the brain easily. Inorganic mercury produces its toxic effects by altering membranes. Mercury inhibits energy metabolism by interacting with several enzyme systems that contain sulfur and by effects on chemicals including lipoic acid. with some descriptions of assaultive and homicidal aggression. symptoms of intoxication relate predominately to that organ. mercury is very slowly eliminated. bound to plasma proteins and hemoglobin. but this syndrome involves generalized irritability and dysautonomia and has no associated movement disorder. These symptoms may be interrupted or accompanied by periods of excitability and irritability. The intoxication occurred after humans consumed contaminated sea food. Unlike lead. Over 6000 patients were hospitalized for treatment. Once incorporated into the nervous system. optic neuritis and atrophy of the optic nerve. The onset of illness may be subtle with postural and kinetic tremor. The presence of tremor has been frequently associated with exposure to mercury. In chronic exposure. accompanied by weakness of the limbs and often a progressive personality change. At the cellular level. the intoxication syndrome seen after organic mercury exposure largely mimics the signs seen with inorganic exposure. Inorganic mercury has remarkable affinity for the kidney. After effluent containing inorganic mercury from an adjacent chemical plant was deposited in sea water. Clinical Syndromes of Intoxication Acute poisoning does not cause movement disorders but is associated with neurological signs that include emotional irritability. coenzyme A. as a result of ingestion of fish and shellfish containing methyl mercury. and this syndrome can be associated with additional signs that include vertigo. less than 3% is degraded into inorganic brain mercury. no association between chronic mercury exposure and Parkinson’s disease was found. and peripheral neuropathy. With acute intoxication. and pantetheine. $10% of the body burden localizes in the brain. apathy. It is absorbed from the skin and the gastrointestinal and respiratory tracts. alkyl mercury compounds share many of the biochemical effects of their inorganic counterparts and form complexes with sulfhydryl radicals. and methyl mercury so formed was incorporated into the protein of fish and shellfish. Occasionally a clinical picture resembling Parkinson’s disease with slowness. Brain uptake varies. Once biotransformation to inorganic mercury occurs. Blood concentrations below 100 mg lÀ1 are considered to be safe. In 1972. . and 459 known fatalities occurred. but in a large case–control study. Ataxia and gait instability has also been described in the context of chronic mercury exposure. nystagmus. Anatomic changes in the brain involve especially the primary visual cortex and cerebellum followed by the putamen and frontal/parietal lobes. Massive intoxication occurred in individuals living in the vicinity of Minamata Bay. gait difficulty. The blood–brain barrier provides little impediment to the crossing of alkyl mercurials. Because organic mercury is converted to inorganic metal. Urinary excretion is similarly an untrustworthy measure of toxicity. particularly through combination with sulfur-containing bonds. mercury was methylated by microorganisms in the sediment. nonionized mercury is transported in the blood. The hyperirritability can be associated with violent behaviors. In children. principally as a result of eating homemade bread prepared from seed treated with a methyl mercury fungicide.172 Mercury mercury volatilizes at room temperature and condenses on skin and respiratory membranes. and tremor develops. chronic inorganic mercurialism is associated with acrodynia. narrowing of the visual fields. Japan. blurred vision. Alkyl mercury remains bound to protein for long periods as the half-life is several years. but under appropriate conditions. hallucinations. Other involuntary movements are described but have been poorly characterized in the literature. mercury forms complexes with amino groups of proteins. and insomnia. another catastrophic epidemic of methyl mercury poisoning occurred in Iraq. Alkyl mercury poisoning has followed the ingestion of contaminated sea food or exposure to alkyl mercury used in seed grain as an antifungal additive. The chronic form of mercurialism is more common and occurs in industries that use mercury in low doses. and brain turnover is slow. psychosis with delirium. but this rate may change with chronic exposure. Peripheral nerves are also damaged. the brain incorporates mercury rapidly. but toxic symptoms are usually present when concentrations exceed 500 mg lÀ1. rigidity. far more often than in adults. but tremor intensity and frequency had not been definitely correlated with current urinary levels of mercury.

and Beuter A (2006) Quantitative tremor assessment in workers with current low exposure to mercury vapor. so they can be administered orally to bind mercury in bile and other fluids within the intestine. Less frequent movement disorders include resting or postural tremor. presumably as a result of rapid mobilization from the tissues and a slower rate of urinary and fecal excretion. Mooney HS. head samples must be taken close to the scalp and then washed to remove contaminants such as hair dyes or hair treatments. Subclinical slowing of finger tap speed has been detected in subjects with regular high fish consumption and levels of urinary organic and inorganic mercury that were higher than controls. iron. and poor coordination. mercury concentrations of blood increase for 1–3 days. copper. many patients demonstrate evidence of cerebellar involvement. Diagnosis It is difficult to diagnose mercury toxicity from laboratory data because of variability of blood and urine measurements. Annals of Neurology 24: 651–659. Hair samples must be collected according to specific protocols. Richer F. slurred speech.movementdisorders. London: Arnold. The advantage of hair samples is that they provide exposure information for the past year. 181–200. Sallsten G. and Peterson EL (1999) Occupational exposure to manganese. potentially adverse systemic effects. mental deterioration. Dimer-caprol (BAL) is no longer utilized. Because thiol resins cannot reenter the body. While measurements in blood and hair are less variable than those in urine. Administration of chelating agents results in only irregular removal of mercury from the body. n-acetyl-DL-penicillamine.) Medical Neurotoxicology. mercury and zinc and the risk of Parkinson’s disease. Sharma DC (1987) Biochemical basis of the toxicity of mercury. Examples have also been reported of ataxic. chorea. Wastensson G. In urine. Rybicki BA. Kallenbach LR. Tremor. lead. toxicologic. improvement may occur within the first 6 months. ` s C. and Fieldler KJ (1994) Methyl mercury poisoning: Long-term clinical. especially children and young adults. For example. but still far lower than the levels cited above. Further Reading Albers JW. International Archives of Occupational and Environmental Health 80: 381–387. . Kazantzis G (2002) Mercury exposure and early effects: An – Movement Disorder Society. Neurotoxicology and Teratology 27: 245–257. Neurotoxicology 24: 617–623. mercury-binding compounds augment excretion of the metal in intoxicated patients regardless of the type of mercury exposure. and Ibba A (2003) Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through fish consumption. Pubic hair has the advantage of being more likely free of mercury-containing surface contaminants. and pathologic studies of an affected family. Athetosis. Neurotoxicology 20: 239–247. Carta P. and some children who were totally blind regained vision. levels higher than 35 mg gÀ1 creatinine are considered elevated. and blindness. Prominent behavioral problems include labile affect. Johnson CC. When chelating agents are administered. pp. and Poitras K (2005) Neuromotor Despre functions in Inuit preschool children exposed to Pb. and thiol resins. visual field defects. and Fine LJ (1988) Neurological abnormalities associated with remote occupational elemental mercury exposure. Fecal excretion is then enhanced by preventing reabsorption of methyl mercury so that redistribution of mercury in the body will not occur. Prognosis Most patients with severe mercury poisoning die within a few weeks of symptom onset. blood concentrations decline. and even akinetic mutism. Davis LE. comatose states. Feng X. Yoshida M. After this period. Flore C. See also: Ataxia. and those who survive have major neurological disability. athetosis. Kornfeld M. Gorell JM. and rigidity. In those with mild or moderate neurological symptoms. The agents employed include D-penicillamine. bedridden individuals who regained the ability to walk. Treatment For treatment.Mercury 173 The primary neurological syndrome of this form of intoxication involves neuropathy. Neurotoxicology and Teratology 28: 681–693. The protective effect appears to be related to increasing stool excretion through a yet unknown mechanism. Medical Hypotheses 23(3): 259–263. PCBs and Hg. Beuter A. and Liu XJ (2007) Effects of mercury vapor exposure on neuromotor function in Chinese minors and smelters. Goetz CG and Washburn KR (1999) Metals and neurotoxicology. Lamoureux D. these do not accurately reflect the degree of mercury toxicity. radiological. they have no Relevant Websites www. with unsteady gait. Annals of Neurology 35: 680–688. Sakamoto M. myoclonus. Thiol resins are not absorbed from the gastrointestinal tract. In: Blain PG and Harris JB (eds. Chorea. Spironolactone has also been employed in the experimental treatment of inorganic mercury poisoning. because it increased the cerebral mercury concentrations in animals experimentally receiving the methyl form. Alinovi R. Medicina del Lavoro 93: 139–147. Iwata T.

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