BioWorld International Correspondent

LONDON - Neurodegenerative disorders such as Parkinson's disease may be due to an imbalance between the generation of new neurons throughout life and the death of neurons, a team of researchers in Sweden suggests.

The scientists, whose experiments in mice have shown that neural stem cells naturally replenish the dopamine-producing nerve cells that are lost in people with Parkinson's disease, said their finding opens up a new field of research to investigate how the brain regulates that process.

Ann Marie Janson, associate professor in the department of neuroscience at the Karolinska Institute in Stockholm, told BioWorld International, "Our observations could provide an alternative explanation for very slow neurodegenerative disorders such as Parkinson's disease. We know that these conditions go on for years and years, and that people slowly lose their population of nerve cells in the substantia nigra of the brain. Our animal experiments suggest that this could be due to too little production of new neurons rather than just that these cells die off."

An account of the group's studies is published in the June 3, 2003, Proceedings of the National Academy of Sciences in a paper titled "Evidence of neurogenesis in the adult mammalian substantia nigra."

The group is working on establishing what factors and signals control the process by which neural stem cells differentiate into dopamine-producing nerve cells, and migrate to the substantia nigra.

"We do not want to raise false hopes, but our discovery that there is an endogenous turnover of cells in this part of the mammalian brain suggests that it may be possible to stimulate this process in people suffering from Parkinson's disease," Janson said. "If we can find out what substances regulate this process, then there would be high hopes of having a new remedy for this disease. But first we need to do many more animal experiments."

The starting point for the team's work was the observation that the total number of nerve cells in the substantia nigra of adult mice did not change throughout the animals' lives, even though some were found to die. After devising a method for counting and identifying new nerve cells in that part of the brain, the team was able to show that new neurons were derived from neural stem cells from a structure called the cerebroventricular surface, which is located deep in the midbrain.

Further studies demonstrated that streams of cells ran from the cerebroventricular surface into the substantia nigra, and that the cells along that path were positive for markers associated with immature neurons. The migrating cells, the team subsequently showed, ended up as dopamine-producing neurons in the substantia nigra.

Scientists have observed before that the mammalian brain produces new neurons during adult life. In adult rats, part of the hippocampus is thought to produce about 10,000 new neurons every day, for example.

So why had no one spotted this process happening in the substantia nigra before? Janson believes the replenishment of cells has been overlooked because it is so slow. She said, "Our data show that under conditions where a mouse forms 10,000 new nerve cells in the hippocampus, the same animal generates only about 22 new dopamine nerve cells in the substantia nigra. But you have to remember that the total population of nerve cells in the subregion of the hippocampus where neurogenesis is known to occur is over 0.5 million, while there are only around 12,000 nerve cells in the substantia nigra."

Janson and her colleagues carried out further experiments to confirm that the new nerve cells really were new and that they had not confused the characteristics of these new cells with pre-existing cells that were simply repairing themselves. They also showed the newly generated cells extended axons to other parts of the brain, as cells of the substantia nigra normally do, and that the axons connected to the correct circuits within the brain.

Perhaps most importantly, they also showed that if they created a small lesion in the substantia nigra, they could increase the subsequent rate of neurogenesis.

"This is probably the most important take-home message of this paper," Janson said. "Our ability to increase the formation of new neurons shows that it is possible to upregulate this process, and that it is not a fixed process that cannot be influenced in any way."

She predicted that the finding will "open up a new box of questions that we and, we hope, other research teams will try to answer. We need to know what are the signals that contribute to neurogenesis in the substantia nigra, what regulates this process, and how we can manipulate it in order to increase the proliferation, migration and differentiation of neural stem cells to generate new neurons in this important relay station for motor behavior in the mammalian brain."