Neuromelanin (NM) is a dark
pigment
A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compo ...
found in the brain which is structurally related to
melanin
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
. It is a
polymer
A polymer (; Greek '' poly-'', "many" + ''-mer'', "part")
is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...
of
5,6-dihydroxyindole
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
monomers.
Neuromelanin is found in large quantities in
catecholaminergic cells of the
substantia nigra pars compacta and
locus coeruleus
The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system.
The locus coerule ...
, giving a dark color to the structures.
Physical properties and structure
Neuromelanin gives specific brain sections, such as the substantia nigra or the locus coeruleus, 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 staining In pathology, silver staining is the use of silver to selectively alter the appearance of a target in microscopy of histological sections; in temperature gradient gel electrophoresis; and in polyacrylamide gels.
In traditional stained glass, silv ...
. 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 aging, noticeably after 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
A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing.
Ageing
Ailments of unknown cause
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabo ...
structure and it avidly
chelates
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...
metals.
Synthetic pathways
Neuromelanin is directly biosynthesized from
L-DOPA
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
, precursor to
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
, by tyrosine hydroxylase (TH) and
aromatic acid decarboxylase (AADC). Alternatively,
synaptic vesicles
In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impul ...
and endosomes accumulate
cytosolic
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
dopamine (via
vesicular monoamine transporter 2
The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the ''SLC18A2'' gene. SLC18A2 is an integral membrane protein that transports monoamines—particul ...
(
VMAT2
The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the ''SLC18A2'' gene. SLC18A2 is an integral membrane protein that transports monoamines—particul ...
) and transport it to
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
where it is metabolized by monoamine oxidase. Excess dopamine and DOPA molecules are oxidized by iron catalysis into
dopaquinone
-Dopaquinone also known as ''o''-dopaquinone is a metabolite of L-DOPA (L-dihydroxyphenylalanine) and a precursor of melanin.
Biosynthesis of melanin occurs in melanocytes, where tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxy ...
s and semiquinones which are then phagocytosed and are stored as neuromelanin.
Neuromelanin biosynthesis is driven by excess
cytosolic
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
catecholamines
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a substi ...
not accumulated by synaptic vesicles.
Function
Neuromelanin is found in higher concentrations in humans than in other
primate
Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...
s.
Neuromelanin concentration increases with age, suggesting a role in
neuroprotection
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
(neuromelanin can
chelate
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...
metals and
xenobiotic
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
s) or senescence.
Role in disease
Neuromelanin-containing
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s in the substantia nigra undergo neurodegeneration during
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. Motor symptoms of Parkinson's disease are caused by cell death in the substantia nigra, which may be partly due to
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. This oxidation may be relieved by neuromelanin. Patients with Parkinson's disease 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
The pars compacta (SNpc) is a portion of the ''substantia nigra'', located in the midbrain. It is formed by dopaminergic neurons and located medial to the pars reticulata. Parkinson's disease is characterized by the death of dopaminergic neurons ...
, and locus coeruleus have been linked to Parkinson's disease and also have been visualized ''in vivo'' with
neuromelanin imaging.
Neuromelanin has been shown to bind neurotoxic and toxic metals that could promote neurodegeneration.
History
Dark pigments in the substantia nigra were first described in 1838 by
Purkyně, and the term neuromelanin was proposed in 1957 by Lillie, 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.
References
{{Reflist, 30em
Biological pigments
Neurochemistry