Molecular Markers of Dopamine Transport in Nigrostriatal Dopaminergic Neurons as an Index of Neurodegeneration and Neuroplasticity

Abstract

Excessive accumulation of dopamine (DA) in the cytosol, which becomes cytotoxic after oxidation, causes degeneration of dopaminergic (DA-ergic) neurons in Parkinson’s disease. The cytosolic DA content is a result of several processes, including vesicular deposition and DA reuptake. Taking this into account, in the present study we examined the expression of genes and proteins of type 2 vesicular monoamine transporter (VMAT2) and DA membrane transporter (DAT) in nigrostriatal DA-ergic neurons. We studied normal mice and mice with 29 or 59% degeneration of DA-ergic neurons induced by 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), whose precursor is converted into a toxin in the brain. When extrapolating data from the study of the substantia nigra to the neuron, we showed that the degeneratSion of one-third of neurons resulted in the increased expression of the DAT gene in the surviving neurons and a reduced content of DAT; however, the expression of the gene decreased, while the content of VMAT2 increased. The decrease in the content of DAT and the increase in the content of VMAT2 indicate a decrease in DA reuptake and an increase in DA vesicular storage, which contributes to a decrease in cytosol accumulation of DA. Degeneration of a larger number of DA-ergic neurons was followed by an increased content of VMAT2, which indicates an increase in vesicular storage and an even greater reduction in the risk of cytosolic accumulation of oxidized DA. When extrapolating the data of the study in the striatum to the DA-ergic axon, we found that the content of DAT in the preserved axons did not change compared to the control, while the content of VMAT2 decreased, which indicates a decrease in vesicular storage of DA. Given the increased DA synthesis and the unchanged level of DA reuptake, a decrease in the content of VMAT2 should lead to the accumulation of oxidized toxic forms of DA in the cytosol.