BioWorld International correspondent

LONDON - Angiogenin, a molecule previously known to encourage the growth of blood vessels in tumors, has now been shown to encourage the normal growth and survival of motor neurons.

The discovery provides the first evidence that mutations in the gene encoding angiogenin, observed in some people with motor neurone disease (MND), may be linked to the cause of the disease.

Vasanta Subramanian, senior lecturer at the University of Bath, told BioWorld International: "Our next step will be to try to understand the mechanism by which angiogenin has this nurturing effect on nerve cells, and what goes wrong in MND patients who have mutations in this gene. Ultimately, we would like to have an understanding of the mechanism of action of angiogenin in the nervous system, which could provide the basis to develop therapies."

Subramanian and her colleagues have published a series of papers relating to that topic, most recently in the Oct. 4, 2007, issue of the journal Human Molecular Genetics. The title of the paper is "Human angiogenin is a neuroprotective factor and Amyotrophic Lateral Sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons."

MND, also known as amyotrophic lateral sclerosis, affects up to five of every 100,000 people. It results when the neurons responsible for stimulating muscle movements die, causing muscle weakness and wasting.

The search for genetic causes of MND has been largely disappointing. Although some patients have mutations in the gene encoding the enzyme SOD-1 (superoxide dismutase 1), such mutations account for only 1 or 2 percent of sporadic cases of MND, and only about 20 percent of those with familial MND.

So when a team of researchers in Ireland reported last year that they had found mutations in the gene encoding angiogenin that were associated with both familial and sporadic cases of MND, scientists were interested to know how the mutations had their effect.

"We were intrigued by this finding," Subramanian noted, "because we had been studying angiogenin and had already noted that it was strongly expressed in the nervous system of mice. We set out to discover what it was doing there."

Using a cell culture model that made it possible to grow motor neurons from stem cells, Subramanian and her colleagues examined how and where angiogenin was expressed during the development of the nerve cells.

Having confirmed that angiogenin was expressed during the development of motor neurons, they went on to inhibit its action using a small-molecule inhibitor. Without angiogenin, the developing motor neurons clumped together, and although they developed neurites (axons), those did not move or extend as they would normally, a process sometimes known as pathfinding.

The group went on to produce mutant angiogenin featuring the same mutations as had been observed in some patients. When they added the mutant angiogenin to their cell cultures, they found that it had a similar effect to their inhibition experiments - again, the cells developed neurites (axons) but they simply bunched up and did not extend out away from the cell bodies.

In a further experiment, they subjected the cell cultures to oxidative stress, allowing some to develop in normal air, while others were provided with only low oxygen levels. "We found that when the neurons, which were not supplied with any growth factors, were deprived of oxygen, many of them died," Subramanian said. "When we added angiogenin to these cultures, many of the neurons survived. But if we added mutant angiogenin, this did not have the same neuroprotective effect."

The results suggested, she added, that angiogenin is neuroprotective, and that its mutant form may be cytotoxic. The gradual buildup of the mutant form may explain the late onset and slow deterioration of function that occurs in MND.

The team's target now is to understand more about the normal role of angiogenin in the nervous system. Subramanian said: "We need to know whether angiogenin is secreted by neurons or by other cell types in the nervous system, and how it is taken up. What is its target and what proteins does it interact with?"

Only by understanding the biochemistry of the molecule, she predicted, will it be possible to work out whether it will be a suitable therapeutic target in people with MND.

"We will have to come up with some clever strategies in order to interfere specifically with the mutant angiogenin and not the wild-type version, because we do not want to affect angiogenin's role in the nervous and vascular systems," she concluded.