Neuromelanin

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5,6-dihydroxyindole, the monomer out of which neuromelanin polymers are formed.

Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. Neuromelanin is expressed in large quantities in dopaminergic cells of the substantia nigra, giving dark color to the structure.[1]

Importance in humans[edit]

Neuromelanin is found in higher concentrations among humans than in other primates.[1] Neuromelanin-containing neurons in the substantia nigra undergo neurodegeneration during Parkinson's Disease. Neuromelanin concentration increases with age, suggesting role in either neuroprotection (neuromelanin can chelate metals and xenobiotics+[2]) or senescence.

Synthetic pathways[edit]

Neuromelanin is directly biosynthesized from L-DOPA, precursor to dopamine, by tyrosine hydroxylase (TH) and aromatic acid decarboxylase (AADC). Alternatively, synaptic vesicles and endosomes accumulate cytosolic dopamine (via vesicular monoamine transporter 2 (VMAT2) and transport it to mitochondria where it is metabolized by monoamine oxidase. Excess dopamine and DOPA molecules are oxidized by iron catalysis into quinones and semiquinones which are then phagocytosed and are stored as neuromelanin.[3]

Related disease[edit]

Photomicrograph of a region of substantia nigra in a Parkinson's patient showing Lewy bodies and Lewy neurites. The 20 × magnification image shows strand-like Lewy neurites and rounded Lewy bodies of various sizes. Neuromelanin laden cells of the substantia nigra are visible in the background.

Parkinson's Disease is caused by cell death in the substantia nigra. This cell death may be partly due to oxidative stress. This oxidation may be relieved by neuromelanin. It has been shown that patients with Parkinson's Diseases had 50% the amount of neuromelanin in the substantia nigra as compared to similar patients of their same age but without Parkinson's. The death of neuromelanin containing neurons in the substantia nigra, pars compacta, and locus coeruleus have been linked to Parkinson's Disease and also have been visualized in vivo with Neuromelanin MRI.[4] Neuromelanin has been shown to bind neurotoxic and toxic metals that could promote neurodegeneration. Compared to darker skinned people, White People have lower amounts of neuromelanin. This is why Parkinson's disease and degenerative brain disorders such as dementia are more common among white-skinned populations. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles.[5]

Physical properties and structure[edit]

Neuromelanin gives specific brain sections, such as the substantia nigra, distinct color. It is a type of melanin and similar to other forms of peripheral melanin. It is insoluble in organic compounds, and can be labeled by silver stains. It is called neuromelanin because of its function and the color change that appears in tissues containing it. It contains black/brown pigmented granules. Neuromelanin is found to accumulate during ageing and is found during the first 2–3 years of life. It is believed to protect neurons in the substantia nigra from iron induced oxidative stress. It is considered a true melanin due to its stable free radical structure and it avidly chelates metals.[6]

History[edit]

Neuromelanin was first described in 1838 by Purkyně,[7] though it has been thought to serve no function until recently. It is now believed to play a vital role in preventing cell death in certain parts of the brain. It has been linked to Parkinson's Disease and because of this possible connection, neuromelanin has been heavily researched in the last decade.[8]

References[edit]

  1. ^ a b Fedorow, H; Tribl, F; Halliday, G; Gerlach, M; Riederer, P; Double, K. L. (2005). "Neuromelanin in human dopamine neurons: Comparison with peripheral melanins and relevance to Parkinson's disease". Progress in Neurobiology 75 (2): 109–24. doi:10.1016/j.pneurobio.2005.02.001. PMID 15784302.  edit
  2. ^ Tribl, F; Asan, E; Arzberger, T; Tatschner, T; Langenfeld, E; Meyer, H. E.; Bringmann, G; Riederer, P; Gerlach, M; Marcus, K (2009). "Identification of L-ferritin in neuromelanin granules of the human substantia nigra: A targeted proteomics approach". Molecular & Cellular Proteomics 8 (8): 1832–8. doi:10.1074/mcp.M900006-MCP200. PMC 2722774. PMID 19318681.  edit
  3. ^ Rabey, J. M.; Hefti, F (1990). "Neuromelanin synthesis in rat and human substantia nigra". Journal of neural transmission. Parkinson's disease and dementia section 2 (1): 1–14. doi:10.1007/BF02251241. PMID 2357268.  edit
  4. ^ Sasaki M, Shibata E, Tohyama K, Takahashi J, Otsuka K, Tsuchiya K, Takahashi S, Ehara S, Terayama Y, Sakai A (July 2006). "Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease". NeuroReport 17 (11): 1215–8. doi:10.1097/01.wnr.0000227984.84927.a7. PMID 16837857. 
  5. ^ Stepień, K; Dzierzega-Lecznar, A; Tam, I (2007). "The role of neuromelanin in Parkinson's disease--new concepts". Wiadomosci lekarskie (Warsaw, Poland : 1960) 60 (11-12): 563–9. PMID 18540183.  edit
  6. ^ http://www.uni-leipzig.de/~nfp/Research/Projects/IBA_in_life_sciences/body_iba_in_life_sciences.html
  7. ^ Usunoff, K. G.; Itzev, D. E.; Ovtscharoff, W. A.; Marani, E (2002). "Neuromelanin in the human brain: A review and atlas of pigmented cells in the substantia nigra". Archives of physiology and biochemistry 110 (4): 257–369. PMID 12516659.  edit
  8. ^ Zecca, L; Tampellini, D; Gerlach, M; Riederer, P; Fariello, R. G.; Sulzer, D (2001). "Substantia nigra neuromelanin: Structure, synthesis, and molecular behaviour". Molecular pathology : MP 54 (6): 414–8. PMC 1187132. PMID 11724917.  edit