Abstract:

Although the exact mechanism(s) of the degeneration of dopaminergic neurons in PD is not well understood, mitochondrial dysfunction is proposed to play a central role. This proposal is strongly strengthened by the findings that compromised mitochondrial functions and/or exposure to mitochondrial toxins such as rotenone, paraquat, or MPTP causes degeneration of the mid brain dopaminergic system and manifest symptoms similar to Parkinson’s in primates and rodents. In fact, the specific dopaminergic toxin MPTP is one of the most commonly used models in the mechanistic studies of environmental factors associated with the etiology of PD, particularly due to the availability of direct and unequivocal clinical and biochemical evidence from human and primate subjects. Several decades of intense studies in many laboratories have led to a general mechanism for thespecific dopaminergic toxicity of MPTP. The salient features of this mechanism are (a) lipophilic pro-toxin MPTP freely crosses the blood brain barrier and enters the brain; (b) in glial cells monoamine oxidase-B converts it to the terminal toxin MPP+; (c) the polar MPP+ is extruded into the extracellular space through organic cation transporter-3; (d) presynaptic dopamine transporter (DAT) takes it upspecifically into dopaminergic neurons; (e) in dopaminergic neurons, MPP+ accumulates in the synaptic vesicles and/or mitochondria; (f) mitochondrial MPP+ inhibits the mitochondrial complex-I of the electron transport chain leading to cellular ATP depletion and excessive ROS production causing apoptotic cell death. Although this mechanism is generally well accepted, numerous recent studies seriously challenge the central dogma of this proposal that the specific dopaminergic toxicity of MPP+ is primarily due to the specific uptake into dopaminergic neurons through presynaptic DAT.