The researchers reported in the February issue of Nature Genetics that mice lacking the gene for iron regulatory protein 2 (IRP2) develop iron deposits in key areas of the brain. The progressive deterioration of the mice's nervous system is like that seen in people with Parkinson's Disease and Multiple System Atrophy (also known as Parkinson's Plus).
"Researchers have long debated whether the characteristic iron deposits of these diseases are the cause or the result of the disease process," said Duane Alexander, M.D., Director of the NICHD. "This is a strong clue that iron may play a causative role in Parkinson's and similar disorders."
Diseases in which excess brain iron has been observed include Parkinson's Disease, Friedreich's Ataxia and Hallervorden-Spatz disease. However, the brain areas affected differ from those in the IRP 2 deficient mice, and it is unlikely that IRP 2 is involved in these human diseases, said the study's senior investigator, Tracey A. Rouault, M.D., of NICHD's Cell Biology and Metabolism Branch. Still, the NICHD finding suggests that other genes involved in iron metabolism may be good candidates for investigations into the causes of these disorders.
In addition, the brain areas affected in the IRP 2 deficient mice correspond closely to those affected in Multiple System Atrophy (formerly known as Olivopontocerebellar Atrophy). For this reason, the NICHD researchers are planning a study to test patients with this disorder for defects of the IRP2 gene.
IRP 2 is a key player in regulating how much iron is in the cell, Dr. Rouault explained. Although iron is a nutrient, too much can also be toxic. For this reason, cells have intricate biochemical machinery to prevent iron from building up to lethal levels. Like its sister protein, iron regulatory protein 1, IRP 2 governs the actions of various other proteins involved in iron metabolism. These include transferrin receptor, which transports iron into the cell; ferritin, which stores iron safely away from the cell's internal machinery; and iron exporters, which ferry iron out of the cell.
Using a method known as "knockout technology," the researchers developed a strain of mice lacking the IRP 2 gene. These mice developed normally at first, then progressively had difficulty walking and moving. Examination of their brains showed that tiny clumps of iron accumulate in the cerebellum, the brain structure controlling movement, and in the basal ganglia, the group of brain cells atop the spinal cord, which assist in movement. These mice also had high blood levels of the iron storage protein ferritin.
"In the corresponding human diseases, you see only the end result," Dr. Rouault said. "With these mice, we know that the primary event is removal of the gene."
Currently, Dr. Rouault is seeking patients with Multiple System Atrophy to take part in a genetic study to learn whether they have a genetic defect involving IRP 2. Similarly, she is also seeking patients with Parkinsonian symptoms for the study, because Multiple System Atrophy often masquerades as Parkinson's. Dr. Rouault and her colleagues are especially interested in seeing patients with these diseases who have relatives with either disorder and have high blood levels of ferritin. Those wishing to participate may have their physicians contact Dr. Rouault at Rouault@mail.nih.gov or write her at the Cell Biology and Metabolism Branch, NICHD, Bldg. 18T, Room 101, Bethesda, MD 20892.
The NICHD is part of the National Institutes of Health, the biomedical research arm of the Federal government. The Institute sponsors research on development before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD website, http://www.nichd.nih.gov, or from the NICHD Clearinghouse, 1-800-370-2943; E-mail NICHDClearinghouse@mail.nih.gov.
The National Institute of Neurological Disorders and Stroke provides information on the neurological disorders mentioned in this release on its website.
Multiple system Atrophy (Olivopontocerebellar Atrophy)