Neuromelanins in brain aging and Parkinson's disease: synthesis, structure, neuroinflammatory, and neurodegenerative role

Abstract

Neuromelanins are compounds accumulating in neurons of human and animal brain during aging, with neurons of substantia nigra and locus coeruleus having the highest levels of neuromelanins. These compounds have melanic, lipid, peptide, and inorganic components and are contained inside special autolysosomes. Neuromelanins can participate in neuroprotective or toxic processes occurring in Parkinson's disease according to cellular environment.Their synthesis depends on the concentration of cytosolic catechols and is a protective process since it prevents the toxic accumulation of catechols-derived reactive compounds. Neuromelanins can be neuroprotective also by binding reactive/toxic metals to produce stable and non-toxic complexes. Extraneuronal neuromelanin released by dying dopamine neurons in Parkinson's disease activates microglia which generate reactive oxygen species, reactive nitrogen species, and proinflammatory molecules, thus producing still neuroinflammation and neuronal death. Synthetic neuromelanins have been prepared with melanic, protein structure, and metal content closely mimicking the natural brain pigment, and these models are also able to activate microglia.Neuromelanins have different structure, synthesis, cellular/subcellular distribution, and role than melanins of hair, skin, and other tissues. The main common aspect between brain neuromelanin and peripheral melanin is the presence of eumelanin and/or pheomelanin moieties in their structure.

A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

“…The synthesis of neuromelanin is a normal and harmless process that also has a neuroprotective role by preventing the neurotoxic effects of reactive metals. However, neuromelanin released from dead dopaminergic neurons is able to activate microglia, generating proinflammatory molecules and reactive oxygen and nitrogen species [ 42 ]. Neuromelanin injected into the substantia nigra of rats induces microglia activation and loss of tyrosine hydroxylase-positive neurons [ 43 ].…”

Chemiexcitation: Mammalian Photochemistry in the Dark†

“…3 The catechol ring is also present in catecholamine neurotransmitters such as dopamine and norepinephrine. 4 Neuromelanins are polymers of eumelanin and pheomelanin assembled from oxidized serotonin, dopamine, norepinephrine, or related neurotransmitters, bound to protein and dolichol lipid in autolysosomes within neurons (114). They are found in the brain's premotor cortex, cerebellum, putamen, substantia nigra, locus coeruleus, dorsal nucleus of the vagus, and raphe nuclei (115).…”

“…This specificity can be provided by chemiexcitation's requirement for Á NO and O 2 Áplus a dioxetane host like melanin. A causal role for neuromelanin has long been suggested: The substantia nigra neurons lost are those containing (114,209,225,226). The nigra's neuromelanin derives from dopamine and occurs in autolysosomes rather than melanosomes (227).…”

“…Each can form a dioxetane or shows evidence of doing so (112,113). The pyrrole ring is a key component of the heme porphyrin ring and of heme‐cofactor enzymes such as cytochrome c oxidase, whose function again involves electron transfer. The catechol ring is also present in catecholamine neurotransmitters such as dopamine and norepinephrine. Neuromelanins are polymers of eumelanin and pheomelanin assembled from oxidized serotonin, dopamine, norepinephrine, or related neurotransmitters, bound to protein and dolichol lipid in autolysosomes within neurons (114). They are found in the brain's premotor cortex, cerebellum, putamen, substantia nigra, locus coeruleus, dorsal nucleus of the vagus, and raphe nuclei (115).…”

“…Inflammation and ischemia–reperfusion injury generates · NO, O 2 ·– , and ONOO − broadly across tissues (34), yet the cells that die or over‐proliferate are only those containing melanin or neuromelanin: Melanosomes are present in the retinal pigment epithelium (RPE), cochlea, and heart. Neuromelanins accumulate without melanosomes in the human brain's substantia nigra, locus coeruleus, dorsal nucleus of the vagus, and raphe nuclei (Table 1), some of which have been chemically and structurally characterized (114). These melanin‐containing epithelia and neurons are in fact the cells that die from macular degeneration, deafness induced by noise or drugs, Parkinson's disease, and Alzheimer's.…”