Nature 334, 345 - 348 (28 July 1988); doi:10.1038/334345a0

Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease

Etienne Hirsch^*, Ann M. Graybiel^†‡ & Yves A. Agid^*

^* INSERM U289, Laboratoire de Medecine Experimentale, Hôpital de la Salpêtrière, 47 Bd. de I'Hôpital, 75013, Paris, France
^† Department of Brain and Cognitive Sciences, Whitaker College, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
^‡ To whom correspondence should be addressed.

In idiopathic Parkinson's disease massive cell death occurs in the dopamine-containing substantia nigra^1,24. A link between the vulnerability of nigral neurons and the prominent pigmentation of the substantia nigra, though long suspected, has not been proved². This possibility is supported by evidence that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite MPP⁺, the latter of which causes destruction of nigral neurons, bind to neuromelanin^3,4. We have directly tested this hypothesis by a quantitative analysis of neuromelanin-pigmented neurons in control and parkinsonian midbrains. The findings demonstrate first that the dopamine-containing cell groups of the normal human midbrain differ markedly from each other in the percentage of neuromelanin-pigmented neurons they contain. Second, the estimated cell loss in these cell groups in Parkinson's disease is directly correlated (r = 0.97, P = 0.0057) with the percentage of neuromelanin-pigmented neurons normally present in them. Third, within each cell group in the Parkinson's brains, there is greater relative sparing of non-pigmented than of neuromelanin-pigmented neurons. This evidence suggests a selective vulnerability of the neuromelanin-pigmented subpopulation of dopamine-containing mesencephalic neurons in Parkinson's disease.

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