Selectivity of the Parkinsonian neurotoxin MPTP: Toxic metabolite MPP ⁺ binds to neuromelanin

Methylphenyltetrahydropyridine (MPTP) selectively destroys neuronal cell bodies in the melanin-containing substantia nigra of humans and other primates. We show that methylphenylpyridine (MPP⁺), an active metabolite of MPTP which is accumulated intraneuronally by the catecholamine uptake system, binds with high affinity to melanin and neuromelanin. MPP⁺ bound intracellularly to neuromelanin may be released gradually, resulting in subsequent damage to the neurons of the substantia nigra.