Molecular and neurochemical mechanisms in PD pathogenesis

Oxidation of dopamine to aminochrome seems to be a normal process leading to aminochrome polymerization to form neuromelanin, since normal individuals have this pigment in their dopaminergic neurons in the substantia nigra. The neurons lost in individuals with Parkinson's disease are dopaminergic neurons containing neuromelanin. This raises two questions. First, why are those cells containing neuromelanin lost in this disease? Second, what is the identity of the neurotoxin that induces this cell death? We propose that aminochrome is the agent responsible for the death of dopaminergic neurons containing neuromelanin in individuals with Parkinson's disease. The normal oxidative pathway of dopamine, in which aminochrome polymerizes to form neuromelanin, can be neurotoxic if DT-diaphorase is inhibited under certain conditions. Inhibition of DT-diaphorase allows two neurotoxic reactions to proceed: (i) the formation of aminochrome adducts with alpha-synuclein, which induce and stabilize the formation of neurotoxic protofibrils; and (ii) the one electron reduction of aminochrome to the neurotoxic leukoaminochrome o-semiquinone radical. Therefore, we propose that DT-diaphorase is an important neuroprotective enzyme in dopaminergic neurons containing neuromelanin.