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Aug 01, 2023

Link shown between Parkinson's, red/yellow brain pigment

Patients have lower levels of antioxidant black/brown pigment in substantia

Patients have lower levels of antioxidant black/brown pigment in substantia nigra

by Steve Bryson, PhD | March 24, 2023

People with Parkinson's disease have higher than normal levels of a nerve cell-damaging red/yellow pigment called pheomelanin in their substantia nigra, the area of the brain that's mainly affected by the neurodegenerative disease, a study showed.

By contrast, levels of eumelanin — an antioxidant black/brown pigment responsible for the darker color of the substantia nigra — were much lower in Parkinson's patients relative to healthy people.

These findings build on an earlier study by the same research group showing that genetic variants linked to ginger hair and fair skin, as well as a higher risk of skin cancer (melanoma), reduce dopamine production in the substantia nigra.

Dopamine is the major brain chemical messenger that's progressively lost in people with Parkinson's, leading to its disease symptoms. It's also the molecule from which pheomelanin and eumelanin are formed.

"At the present, we do not know if it is just a coincidence, or if brain pigment is part of the body's pigmentation system, regulated by the same signaling pathway," Xiqun Chen, MD, PhD, the study's senior author with the neurology department at Massachusetts General Hospital, said in a news release. "It is even more intriguing given the fact that Parkinson's disease and melanoma are risk factors for each other."

The findings may prompt more research on pheomelanin and eumelanin as biomarkers or therapeutic targets in Parkinson's, the researchers noted in "DOPA pheomelanin is increased in nigral neuromelanin of Parkinson's disease," which was published in Progress in Neurobiology.

Parkinson's disease is caused by the death of dopamine-producing, or dopaminergic, neurons in the substantia nigra, which controls movement and coordination.

Meaning "black substance" in Latin, the substantia nigra is darker than the surrounding pinkish-gray brain tissue. Its darker color is due to neuromelanin, the brain pigment derived directly from dopamine or its precursor L-DOPA.

While neuromelanin formation differs from that of melanin — a structurally similar pigment responsible for producing skin and hair pigmentation — they’re both divided into two types: black/brown eumelanin and red/yellow pheomelanin.

Eumelanin, an antioxidant and more stable form, is responsible for darker skin and hair color. Increased phaeomelanin, a form that can promote oxidative stress, results in reddish or blonde hair and fair skin.

Oxidative stress is a type of cellular damage implicated in several neurodegenerative diseases, including Parkinson's. It results from an imbalance between the production of potentially harmful oxidant molecules and the cells’ ability to clear them with antioxidants.

Building on their earlier work, Chen's team, along with collaborators in Italy and Japan, examined levels of neuromelanin, pheomelanin, and eumelanin in the brain tissue of 12 deceased Parkinson's patients, ages 70-74.

Brain tissue from eight healthy adults, ages 68-73, was also assessed, alongside samples from 11 adults, ages 65-74, with Alzheimer's disease, a neurodegenerative disease that's not known to affect dopaminergic neurons in the substantia nigra.

As expected, Parkinson's patients had markedly less dopamine in their substantia nigra than healthy controls. Parkinson's samples also had 30% less L-DOPA than controls, but this difference failed to reach statistical significance. This was likely due to the use of standard levodopa treatments that deliver L-DOPA, the researchers noted.

Consistent with previous studies, neuromelanin levels were significantly lower in the substantia nigra of Parkinson's patients than controls. No major differences in dopamine, L-DOPA, and neuromelanin were detected between Parkinson's and Alzheimer's samples.

Dopamine-derived red/yellow pheomelanin was significantly higher in Parkinson's substantia nigra tissue than in samples from healthy controls and Alzheimer's patients. No differences were seen between control and Alzheimer's tissue.

In contrast, dopamine-derived black/brown eumelanin was significantly lower in Parkinson's samples versus those from controls, even after adjusting for dopamine levels. While L-DOPA-derived eumelanin was also lower, the differences disappeared with L-DOPA adjustments. Controls and Alzheimer's patients had similar eumelanin levels.

To investigate the impact of these changes, researchers exposed lab-grown human nerve cells to increasing doses of lab-made L-DOPA-pheomelanin or L-DOPA-eumelanin for one day.

They found that pheomelanin treatment promoted nerve cell death in a dose-dependent manner. Eumelanin didn't have any effect on cell survival at any dose. Similar results were obtained with lab-grown mouse nerve cells.

"Together with reduced [dopamine-derived] eumelanin, these findings may indicate a shift of the [neuromelanin] production towards imbalanced pheomelanin and eumelanin" in Parkinson's that results in "oxidative stress," the researchers wrote, noting the results "provide insights into the different roles of pheomelanin and eumelanin in" the underlying mechanisms of Parkinson's, setting in place a foundation to study pheomelanin and eumelanin as biomarkers and therapeutic targets for Parkinson's disease.

The study was funded by the Michael J. Fox Foundation for Parkinson's Research and the Aligning Science Across Parkinson's initiative.