Localization and Density of Transferrin Binding Sites in the Nigrostriatal System of Control Subjects and Patients with Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is characterized by a progressive degeneration, mostly confined to the substantia nigra, of dopaminergic neurons which innervate the striatum. The loss of dopaminergic neurons is most severe in the substantia nigra (SN) pars compacta (50–85%), although neuronal death also occurs to a lesser degree (40–50%) in other groups of dopamine-containing neurons located in the mesencephalon (ventral tegmental area — peri- and retrorubral region — referred to as catecholaminergic cell group A8).1–3 The mechanisms by which dopaminergic cell death occurs in PD remain unknown. Many investigations have indicated that abnormal oxidative metabolism could be involved in the degeneration of these neurons. Excess free radicals are produced in excess in the SN of patients with PD. This overproduction could be due to autooxidation of dopamine, neuromelanin-associated toxicity, and iron.3 Increased iron concentrations have been reported in the SN of PD patients as compared to control subjects.4–11 As this metal can catalyze free radical production, it could be a deleterious and neurotoxic factor promoting oxidative stress and damage to a variety of biological molecules, including lipids, proteins and nucleic acids. Oxidative stress, increased by iron overload, may thus contribute selectively to the death of melanized dopaminergic neurons in the SN of PD patients.9,12–13 Although the mechanisms which account for iron uptake in dopaminergic neurons are unknown at present, a possible pathway for iron to gain access to neurons is the uptake from transferrin (Tf) through a receptor-mediated process.14 A higher density of transferrin receptors on melanized dopaminergic neurons of PD patients could bring a selective accumulation of iron in these cells. To test this hypothesis, we studied the regional distribution and density of [125I]-Tf binding sites in the mesencephalon obtained post mortem from parkinsonian patients and age-matched control subjects, using previously reported techniques.15,16 In control subjects we examined those regions of the basal ganglia to which dopaminergic neurons of the SN are projected.