Role of the Ferroxidase Ceruloplasmin in Iron-Mediated Free Radical Injury in the Substantia Nigra

David, Samuel, Ph.D.
Montreal General Hospital Research Institute, Montreal, Quebec, Canada

Abstract

Dr. Samuel David of Montreal General Hospital will use transgenic (also known
as “knock-out”) mice generated in his laboratory to study the role of ceruloplasmin, an enzyme known to detoxify a form of iron that causes toxic free radicals.  Brains of animals that have had the  gene for ceruloplasmin, “knock-out” will be compared with those of wild-type control to assess the amounts of iron deposits, the numbers of surviving dopaminergic neurons and, finally, the appearance of ubiquitin, a molecule whose presence indicates protein damage in brain sells and is also found in Lewy bodies, the hallmark of Parkinson's disease.  Conclusions from Dr. David’s work could expand our knowledge of the pathogensesis (how and why a disease develops) of Parkinson’s disease.

Progress Report (as of 8/2002)

We carried out work to assess the role of iron in the survival and death of neurons in the substantia nigra, the region of the brainstem that is involved in Parkinson’s disease. This region of the brain contains the highest levels of iron. Iron exists in two forms, ferrous iron and ferric iron. Iron is an essential metal, which is required for a number of biological functions in cells. However, ferrous iron is highly toxic as it can produce free radicals that kill cells. We have identified a new form of an enzyme called ceruloplasmin, which is expressed by astrocytes in the brain. Ceruloplasmin detoxifies ferrous iron by oxidizing it to the ferric form. Since its role in the brain was not fully understood, we made a ceruloplasmin gene knockout mouse. Funds were used to study these mice. We found that these mice that lacked ceruloplasmin had deficits of motor coordination. They also showed increased iron deposition in several regions of the brain including the brainstem and the substantia nigra in particular. Histochemical analysis showed a severe degree of neuronal degeneration of the dopaminergic neurons in the substantia nigra. These results show that abnormalities in the regulation of iron levels in the substantia nigra can contribute to death of neurons. Such mechanisms may contribute to the free radical induced death of nerve cells in Parkinson’s disease. This work was published in the August 1, 2002 issue of the Journal of Neuroscience.

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