Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia

Abstract

Previously we have shown that cell death in the substantia nigra (SN) in Parkinson's disease (PD) is associated with an increase in iron content but a decrease in the level of the iron-binding protein ferritin. Alterations in other metal ion levels were also observed; copper levels were reduced, whereas zinc levels were increased. The importance of these changes in iron, ferritin, and other metal ions in the pathophysiology of PD depends on whether they are specific to the illness. We measured levels of iron, copper, zinc, manganese, and ferritin in postmortem tissue from patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (which shows pathology in the SN and striatum) and Huntington's disease (HD) (which shows pathological changes in the striatum, compared with control subjects). Total iron levels were elevated in areas of the basal ganglia showing pathological changes in these disorders. In particular, total iron content was increased in SN in PD, PSP, and MSA, but not in HD. Total iron levels in the striatum (caudate nucleus and/or putamen) were increased in PSP, MSA, and HD, but not in PD. There were no consistent alterations in manganese levels in the basal ganglia in any of the diseases studied. Copper levels were decreased in the SN in PD and in the cerebellum in PSP, and were elevated in the putamen and possibly the SN in HD. Zinc levels were only increased in PD in the SN, the caudate nucleus, and the putamen. Increased iron levels in basal ganglia were generally associated with increased or normal levels of ferritin (e.g., in the SN in PSP and possibly MSA, and in the putamen in MSA). The exception was PD, in which there was a generalized reductidn in brain ferritin levels, even in the SN. An increase in total iron content appears to be a response to neurodegeneration in affected basal ganglia regions in a number of movement disorders; however, only in PD was there increased total iron levels, decreased ferritin content, decreased copper levels, and an increase in zinc content in the SN. These findings suggest that altered iron handling may occur in the SN in PD. Depending on the form in which the excess iron load exists in the SN in PD, it may contribute to the disease process.