What have we learnt from CDNA microarray gene expression studies about the role of iron in MPTP induced...

There have been numerous hypotheses concerning the etiology and mechanism of dorsal raphe dopaminergic neurodegeneration in Parkinson's disease and its animal models, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-hydroxydopamine. The advent of cDNA microarray gene expression where expression of thousands of genes can be globally assessed has indicated that mechanism of neurodegeneration by MPTP is a complex cascade of vicious circles. One of these is the alteration of genes associated with iron metabolism, a transitional metal closely associated with inducing the formation of reactive oxygen species and inducing oxidative stress. cDNA gene expression analyses support the established hypothesis of oxidative induced neurodegeneration involving iron deposition in substantia nigra pars compacta (SNPC) parkinsonian brains. The regulation of cellular iron metabolism has been further enhanced by the recent discovery of two iron regulatory proteins, IRP1 and IRP2 which control the level of iron with in the cell. When the cellular level of iron increases IRP2 is degraded by ubiquitination and no further iron accumulates. The reverse occurs when the level of iron is low within the cell. Knock-out IRP1 and IRP2 mice have shown that in latter mice brain iron accumulation precedes the neurodegeneration, ataxia and bradykinesia observed in these animals. Indeed MPTP treatment, which results in iron accumulation in SNCP, abolishes IRP2 with the concomitant increase in alpha-synuclein. Iron chelators such as R-apomorphine and EGCG, which protect against MPTP neurotoxicity, prevent the loss of IRP2 and the increase in alpha-synuclein. The presence of iron together with alpha-synuclein in SNPC may be detrimental for dopaminergic neurons. Since, iron has been shown to cause aggregation of alpha-synuclein to a neurotoxic agent. The use of iron chelators penetrating the blood brain barrier as neuroprotective drugs has been envisaged.