Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0233565 (bradykinesia)
 2,352 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.
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PMID:Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. 1117 92

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.
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PMID:What have we learnt from CDNA microarray gene expression studies about the role of iron in MPTP induced neurodegeneration and Parkinson's disease? 1294 50