Melanized Midbrain Dopamine Neurons

The Parkinson's-Reversing Breakthrough

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The midbrain dopaminergic neurons are characterized by the presence of neurome-lanin. Neuromelanin is distributed mostly in cells that synthesize dopamine, norep-inephrine, but not epinephrine, and it is derived from dopamine, dopaquinone, and their oxidized products as well as catecholamines that are not stored in the vesicles (8). Tetrabenazine and reserpine, drugs that block incorporation of dopamine in the presynaptic vesicles, increase accumulation of neuromelanin and over-expression of

vesicular monoamine transporter (VMAT2), which facilitates incorporation of cytoplasmic dopamine into the vesicle, decrease neuromelanin synthesis (8,9).

The dopamine neurons of the VTA and SNpc contain cells that are densely melanized and cells that are nonmelanized. In SNpc, 84% to 98% of cells are melanized, and the ratio between the melanized and nonmelanized neurons in the VTA is about 50:50 (10,11). Almost all of the melanized cells in the SNpc and VTA express tyrosine hydroxylase (TH) protein or mRNA (6,11). The melanized cells degenerate more than the nonmelanized cells (6), and accordingly loss of neurons in the VTA in PD is less severe than in the SNpc (11). In PD, 98% of the dopaminergic neurons in nigrosome 1, located in the ventrolateral tier of the SNpc, degenerate early. As the disease worsens, there is a medial and dorsal spatiotemporal pattern of progression of degeneration, ultimately, to include the dopamine cells of the VTA and the retrorubral nucleus (12,13).

Even though highly melanized dopamine neurons of the SNpc and VTA degenerate the most, the precise role played by neuromelanin in these neurons is unknown. Neuromelanin is proposed to play a role in the neurodegenerative process of dopamine and locus coeruleus (LC) neurons in PD; however, even amidst a densely degenerating group of nigral cells in the ventral and lateral nigrosome regions of the SNpc, pigmented neurons do survive. In the SNpc nigrosomes, 98% of the melanized cells degenerate, whereas, even though almost all LC neurons contain neuromelanin, only about 50% to 63% of melanized cells of the LC degenerate in PD. The most important function of neuromelanin may be to store and regulate iron, copper, zinc, and manganese ions, which play important roles in the normal function of TH and cytochrome a, b, and c within the catecholaminergic neurons (14). Neuromelanin has been proposed to play a neuroprotective role in the normal brain by preferentially sequestering pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat and other neurotoxins, iron, and other metallic ions for a significant duration, but, when this storage capacity is exceeded, the iron and pesticides may act as neurotoxic factors (8,14,15).

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