Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models

Abstract

Neuromelanin (NM) accumulates in catecholamine long-lived brain neurons that are lost in neurodegenerative diseases. NM is a complex substance made of melanic, peptide and lipid components. NM formation is a natural protective process since toxic endogenous metabolites are removed during its formation and as it binds excess metals and xenobiotics. However, disturbances of NM synthesis and function could be toxic. Here, we review recent knowledge on NM formation, toxic mechanisms involving NM, go over NM binding substances and suggest experimental models that can help identifying xenobiotic modulators of NM formation or function. Given the high likelihood of a central NM role in age-related human neurodegenerative diseases such as Parkinson’s and Alzheimer’s, resembling such diseases using animal models that do not form NM to a high degree, e.g., mice or rats, may not be optimal. Rather, use of animal models (i.e., sheep and goats) that better resemble human brain aging in terms of NM formation, as well as using human NM forming stem cellbased in vitro (e.g., mid-brain organoids) models can be more suitable. Toxicants could also be identified during chemical synthesis of NM in the test tube.

Cerebral Iron Deposition in Neurodegeneration

“…Simultaneously, the immune system deteriorates. Thus, in normal aging, a mild neuroinflammation can be anticipated, which may be theoretically related to environmental exposures [37,38]. Inflammation can intensify in neurodegenerative diseases, e.g., Alzheimer's disease (AD) characterized by extracellular plaques (common also in normal aging) that are attacked by iron-rich microglia, which express high levels of nicotinamide adenine dinucleotide phosphate oxidases (NOX) releasing O 2…”

“…PD is the second most common neurodegenerative disease after AD. Age, certain chemicals (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, chlorpyrifos, rotenone, and maneb), and metals are risk factors for sporadic PD [37,38,[289][290][291][292]. Pathological effects include alpha-synuclein aggregation inside Lewy bodies in susceptible neuronal populations, dopaminergic neuronal Fe accumulation in SN, oxidative stress, and SN neuronal loss.…”

“…Enhanced ROS levels, together with increased catalytic labile Fe in aging, mediates oxidation of DA into reactive DA metabolites such as DA-ortho-semiquinone radical (DA-o-SQ • ) and 6-hydroxydopamine that both can further oxidize into quinones. Misfolded and aggregated proteins in the cytosol (e.g., alpha-synuclein) are attacked e.g., by reactive DA-o-SQ • , DA-quinone, or aldehydes (e.g., 3,4-dihydroxyphenyl acetaldehyde (DOPAL) and/or aldehydes generated during lipid peroxidation) that form toxic protein adducts which may serve as starting seeds for the molecular backbone in the NM synthesis [37]. The natural NM backbone also contains cysteinyldopamine.…”

Oxidative Stress in Human Toxicology

“…Old neurons are sensitive to toxic insults and are lost in disease. In their new review, A. Cappucciati et al [ 14 ] hypothesize that xenobiotics somehow disturb the build-up of neuromelanin and/or its protective function, which causes toxicity (including ROS formation) as xenobiotics and endogenous metabolites and excess metals are no longer stored away. The authors review the latest knowledge on neuromelanin biosynthesis, list neuromelanin-interacting xenobiotics, and suggest suitable experimental models for studying neuromelanin-related toxicity [ 14 ].…”

“…In their new review, A. Cappucciati et al [ 14 ] hypothesize that xenobiotics somehow disturb the build-up of neuromelanin and/or its protective function, which causes toxicity (including ROS formation) as xenobiotics and endogenous metabolites and excess metals are no longer stored away. The authors review the latest knowledge on neuromelanin biosynthesis, list neuromelanin-interacting xenobiotics, and suggest suitable experimental models for studying neuromelanin-related toxicity [ 14 ]. The authors question the use of rodents such as mice and rats (devoid or low in neuromelanin) as models when resembling human (high in neuromelanin) degenerative diseases.…”