Elsevier

Progress in Neurobiology

Volume 75, Issue 2, February 2005, Pages 109-124
Progress in Neurobiology

Neuromelanin in human dopamine neurons: Comparison with peripheral melanins and relevance to Parkinson's disease

https://doi.org/10.1016/j.pneurobio.2005.02.001Get rights and content

Abstract

Neuromelanin (NM) is a dark polymer pigment produced in specific populations of catecholaminergic neurons in the brain. It appears in greatest quantities in the human brain, in lesser amounts in some other non-human primates, but is absent from the brain in many lower species. Interest in this pigment has seen a resurgence in recent years because of a hypothesised link between neuromelanin and the especial vulnerability of neuromelanin-containing neurons to cell death in Parkinson's disease (PD). Little is known regarding the biology of neuromelanin. As neuromelanin appears to have characteristics in common with the better studied peripheral melanin pigments this review compares what is known about neuromelanin with melanins found in other body tissues. Unlike peripheral melanins, which are produced in specialised cells called melanocytes and may be transferred to other cell types, neuromelanin granules are believed to be stored in the cell in which they are produced. Neuromelanin granules display a unique, more heterogeneous appearance compared with peripheral melanins. Unlike melanin, neuromelanin is traditionally thought to result from a non-enzymatic synthesis pathway with no known pathway for neuromelanin catabolism. More recent data, however, is indicative of some regulation of neuromelanin synthesis and turnover. By analogy with peripheral melanins, neuromelanin may function in vivo to attenuate the effects of damaging stimuli. Among several possible mechanisms suggested, the ability of neuromelanin to interact with transition metals, especially iron, and to mediate intracellular oxidative mechanisms has received particular attention. Recent data from neuromelanin in the Parkinson's disease brain suggests that this proposed function may be compromised, thus rendering pigmented neurons vulnerable to oxidative damage in this disorder.

Introduction

The origin of the name melanin, from the Greek word melanos (“dark”), is usually attributed to the Swedish chemist Berzelius (Prota, 1992). Melanin in the brain has a similar appearance and structure to cutaneous melanins, and has thus been designated neuromelanin (NM) (Lillie, 1955, Lillie, 1957). Based on their precursor molecules, melanins are classified into four groups:

  • Eumelanin is formed from l-3,4-dihydroxyphenylalanine (l-dopa).

  • Pheomelanin is formed by oxidative polymerisation of 5-S-cysteinyl-dopa or 2-S-cysteinyl-dopa.

  • Neuromelanin is thought to be formed by oxidative polymerisation of dopamine or noradrenaline, with the possible involvement of cysteinyl-derivatives.

  • Allomelanin is formed by the oxidation of polyphenols, such as catechols and 1,8-dihydroxynaphtalene. They are widely spread in fungi and are often nitrogen-free.

Interest in the black melanin pigment produced within specific catecholamine neurons in the human brain has seen a resurgence in recent years. Although much is known about melanins outside the central nervous system, to which neuromelanin is thought to be related, many basic questions remain to be answered about melanins in the brain. A review of nerve cell pigmentation in 1918 commented that “there are more opinions than there are investigators” (Dolley and Guthrie, 1918) and this holds true today. It is unclear why some human dopamine neurons produce an insoluble pigment within their cytoplasm and others do not. There is little information regarding the fate of neuromelanin over the lifespan and little is known about neuromelanin's structure. Consequently, a valid and useful approach to this problem is to consider neuromelanin in terms of what is known about the better-characterised and more prominent peripheral melanins (see Table 1 for comparative summary). For clarity in this review, ‘melanin’ will be used to refer to melanins occurring within the periphery (i.e., outside the central nervous system), and ‘neuromelanin’ (NM) will be used to describe melanins occurring within the central nervous system.

Section snippets

Neuromelanin

Traditionally, NM is thought to be an inert cellular by-product, produced via a simple autoxidation pathway, a hypothesis supported by the failure to link tyrosinase, the rate-limiting enzyme of peripheral melanin synthesis to NM. Recent evidence, however, suggests some regulation for NM production and a possible physiological role in the cell. Elucidation of these basic biological characteristics of NM may provide clues to the aetiology of Parkinson's disease (PD), a common neurodegenerative

Other types of cellular melanins

Melanin is widely distributed throughout the plant and animal kingdoms. The black pigment found in fungi, plants and bacteria, although termed allomelanin, is structurally different to the dopa-derived melanins found in animals. In humans, these heterogenous, macromolecular pigments occur naturally in the hair, the skin, the inner ear, and the iris, choroid and retinal pigmented epithelium of the eye. In vivo, melanins occur as an ill-defined heteropolymer of both eumelanin and pheomelanin and

Chemistry of melanins

Although NM is the focus of this review, a general understanding of melanogenesis and chemistry can be provided by investigation of the synthesis pathway of peripheral melanins and comparison to what is known about NM. The first steps in the investigation of melanin synthesis were not undertaken by molecular biologists, rather by organic chemists. Genetic and enzymatic regulation of melanin production in the periphery has been primarily characterised by the study of fur pigmentation in the

Biological roles of melanins

In peripheral tissues, melanins are thought to function as endogenous mediators of oxidative mechanisms. Thus by analogy, NM may play a similar role within the brain (Double et al., 2002).

Conclusions

Although difficult to analyse, the chemical structure of both peripheral and central melanins has been significantly advanced. Many aspects of the normal biology of NM remain to be clarified, particularly the regulation of NM formation and turnover. For peripheral melanins, enzymatic synthesis and turnover is highly regulated. There is insufficient current evidence to support either enzymatic synthesis or simple autoxidation as the main pathways regulating NM formation. At present there is no

Acknowledgements

We thank E. Kettle for assistance with electron microscopy, and H. Cartwright for preparation of figures. H.F. was a recipient of an Australian Postgraduate Award and F.T. was the recipient of a Ph.D. Scholarship DOC from the Austrian Academy of Sciences. G.H. and K.L.D. were funded by the National Health and Medical Research Council of Australia. Financial support from the Deutsche Parkinson Vereinigung e.V. is gratefully acknowledged. Part of this research was completed within “The National

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