Interaction of neuromelanin with xenobiotics and consequences for neurodegeneration; promising experimental models

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.