The Neuromelanin Question: A Large-Scale Test of Tyrosinase in Human Dopaminergic Neurons

Neuromelanin is the dark pigment that accumulates in the catecholaminergic neurons of the substantia nigra and locus coeruleus — the very neurons that are selectively lost in Parkinson’s disease (PD). Despite its close link to selective neuronal vulnerability, the mechanism by which neuromelanin is formed remains unresolved. One model holds that the pigment arises passively from the oxidation of dopamine; another proposes that it is produced actively by enzymes such as tyrosinase (TYR), the enzyme responsible for melanin synthesis in skin.
Work from the Vila laboratory has shown that transgenic expression of tyrosinase produces a neuromelanin-like pigment in both primate and rodent brain, lending support to an enzyme-driven model. However, direct evidence for tyrosinase and related monooxygenases in the human brain remains limited and contested, in large part because their expression is extremely low and is routinely missed by standard analyses. This project leverages the harmonised datasets of the ASAP CRN Cloud to combine, for the first time at scale, many independent human brain datasets and to search systematically for these rare signals. If a reproducible, disease-associated signal is confirmed, it would support an active, enzyme-driven route to neuromelanin formation — and, because enzymes are druggable, would open a path toward reducing harmful pigment accumulation early in disease.