In a recent study published in Progress in Neurobiology, researchers discover that the substantia nigra of individuals with Parkinson’s disease had a higher concentration of pheomelanin, as well as pheomelanin markers associated with L-3,4-dihydroxyphenylalanine (DOPA) and dopamine, than healthy controls.
Study: OPA pheomelanin is increased in nigral neuromelanin of Parkinson’s disease. Image Credit: Rattiya Thongdumhyu / Shutterstock.com
Autolysosomal organelles accumulate in the catecholaminergic neurons, which are found in the locus coeruleus and substantia nigra of the brain, and contain proteins, lipids, and neuromelanin pigments. The age-related accumulation of neuromelanin pigments occurs in all regions of the brain; however, it is highest in the locus coeruleus and substantia nigra. The depigmentation of the substantia nigra due to the decline in the number of dopaminergic neurons containing these pigments is characteristic of Parkinson’s disease.
The melanic portion of the neuromelanin pigment comprises eumelanin, which is a black/brown pigment, and pheomelanin moieties derived from a two-to-one ratio of dopamine to cysteine. Various catecholic metabolites formed through the oxidation and reduction of dopamine and norepinephrine are believed to be incorporated in the neuromelanin pigments in the locus coeruleus and substantia nigra.
Pheomelanin and eumelanin differ in various aspects other than color, such as metal chelation, redox, and the scavenging of free radicals. While eumelanin plays an antioxidant role, pheomelanin can undergo photodegradation, generate reactive oxygen species (ROS), and reduce antioxidants, each of which can be associated with the pathophysiology of neurological diseases.
About the study
In the present study, researchers investigate post-mortem tissue samples from patients with Parkinson’s disease, Alzheimer’s disease, and healthy controls to examine the levels of pheomelanin and eumelanin components of neuromelanin pigments. In vitro studies on primary cortical neurons from mice and differentiated neuronal cells were also conducted to examine the impact of synthetic DOPA eumelanin and pheomelanin on cell viability and death.
Post-mortem samples of the ventral midbrain were obtained from cohorts comprising individuals who had Parkinson’s disease, Alzheimer’s disease, and no neurological disorders confirmed from neuropathological assessments. These samples were homogenized and analyzed to determine the level of neuromelanin pigments and proportions of pheomelanin and eumelanin moieties.
Primary cortical neurons from mice and differentiated neuronal cells obtained from a neuroblastoma cell line were treated with synthetic DOPA eumelanin and pheomelanin to test the hypothesis that pheomelanin is a neurotoxin while eumelanin is not.
The levels of DOPA pheomelanin in the substantia nigra of individuals with Parkinson’s disease were higher than those in healthy controls. The conversion of dopamine to pheomelanin markers was also elevated.
DOPA- and dopamine-derived eumelanin levels were low; however, DOPA-derived pheomelanin levels were higher than those of the dopamine-derived pheomelanin. Notably, in post-mortem tissue samples from individuals with Alzheimer's disease, melanin-associated markers in the substantia nigra remained unaltered, despite low DOPA levels.
The degeneration of dopaminergic neurons and alterations in the dopamine and DOPA metabolism in individuals with advanced Parkinson’s disease could potentially explain the lower levels of dopamine-derived pheomelanin.
Furthermore, the in vitro tests with differentiated and primary cortical neurons indicated that synthetic DOPA pheomelanin could induce cell death in the neurons, whereas synthetic DOPA eumelanin did not. While these results demonstrated that pheomelanin can induce cell death in neurons, previous studies have shown similar results in primary non-catecholaminergic neurons. Thus, the cytotoxicity of pheomelanin is not specific to the catecholaminergic and dopaminergic neurons in the brain.
The lower DOPA and dopamine levels identified in the post-mortem tissue samples from individuals with Alzheimer’s disease as compared to healthy controls were surprising. However, previous studies have not been able to distinguish any pathology associated with the dopaminergic pathway in the substantia nigra in Alzheimer’s disease patients.
The results of this study add to previous findings from the same team of researchers reporting that overall melanin levels in the skin and hair were significantly lower in individuals with Parkinson’s disease as compared to healthy individuals. Furthermore, these observations establish the role of melanin moieties in the pathology of Parkinson’s disease.
Overall, dopaminergic neurons in the substantia nigra of Parkinson’s patients contained a higher proportion of pheomelanin and lower levels of eumelanin as compared to similar dopaminergic neurons in healthy controls. Furthermore, in vitro experiments using mice and neuroblastoma-derived primary cortical neurons demonstrated that synthetic DOPA pheomelanin caused neuronal cell death while synthetic eumelanin did not, thus suggesting their use as biomarkers and potential treatment targets.