Neuromelanins: a link between brain aging and neurodegenerative diseases

Neuromelanins (NMs) accumulate in large amounts in catecholaminergic neurons of the substantia nigra (SN) and locus coeruleus (LC), which selectively degenerate in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Lower amounts of NMs are also present in other human brain regions. NMs are contained in specialized autolysosomes with lipid bodies, proteins, and metals. Their structure, synthesis, functions, and cellular localization differ from those of melanins in non-nervous tissues. Purified NMs have a complex structure, are composed of melanic moieties, lipids, proteins, and inorganic components, and are insoluble. NMs can exert either a protective or toxic role depending on cellular context. NMs synthesis is driven by cytosolic catecholamines and is a protective process, as it removes excess cytosolic catechols that would otherwise trigger neurotoxicity. NMs can bind reactive/toxic metals, forming stable and non-toxic complexes, thereby playing a neuroprotective role. However, NMs released from degenerating neurons in PD and AD activate microglia, which release reactive species and proinflammatory factors, thereby exacerbating neuroinflammation and neurodegeneration. The major histocompatibility complex class I is present within NM-containing organelles of SN and LC neurons and can bind antigens, presenting them on the neuronal membrane. Subsequently, CD8 + T-cells may target catecholaminergic NM-containing neurons, contributing to neurodegeneration. The loss of NM-containing neurons in PD and AD causes a decrease of NMs concentration within the SN and LC, which can be visualized using magnetic resonance imaging (MRI). NM-sensitive MRI of the SN and LC is increasingly being used for the diagnosis and treatment monitoring of neurodegenerative and psychiatric disorders.