By Sharon Kingman
BioWorld International Correspondent
LONDON ¿ The discovery of a mutant gene whose protein product helps nerve cells survive has raised hopes of developing new treatments for diseases as diverse as multiple sclerosis, Alzheimer¿s disease, AIDS and spinal cord injury.
The gene, which is present in a naturally occurring mutant mouse, comprises a fused version of two genes that are normally separate. Researchers already know the identities of the equivalent human genes and are planning studies to find out if mutations in these genes are present in groups of people who are either predisposed to or protected from a range of neurodegenerative diseases.
Michael Coleman, group leader at the Institute for Genetics at the University of Cologne in Germany, told BioWorld International, ¿It is very unlikely that the same mutation would have happened in humans, but one of these two genes could be altered in some way and this alteration could cause susceptibility to or protection from neurodegenerative disease.¿
In recent years, much research into neurodegenerative diseases has focused on ways of protecting the nerve cell body, Coleman said. His recent discovery suggests, however, that it may be possible to find ways of keeping the rest of the nerve cell healthy, in conditions such as crush injuries of nerves (including spinal cord injury), demyelination (as in multiple sclerosis), viral neuropathy (as in AIDS) and toxic neuropathy, where damage to nerves can limit the dose of chemotherapeutic agents given to treat cancer.
Coleman, together with colleagues in Ancona, Italy, and in Edinburgh, Oxford and Southampton in the UK, reports his results in a paper in Nature Neuroscience titled ¿Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene.¿
If a researcher takes a normal mouse and cuts through a nerve so that the axon that projects from the nerve¿s cell body ¿ where the nucleus is located ¿ is no longer attached, the axon undergoes characteristic degeneration. This is known as Wallerian degeneration, after the scientist Augustus Waller, who first described the phenomenon in 1850.
Wallerian degeneration also seems to occur in many human neurodegenerative diseases or conditions, such as multiple sclerosis and neurotoxic damage caused by anticancer drugs.
About 12 years ago, Hugh Perry and Michael Brown, working at the University of Oxford, discovered that the nerves of a mutant mouse that was otherwise normal were resistant to Wallerian degeneration, taking about 10 times longer to degenerate. They demonstrated that this characteristic was inherited, and set out to track down the mutant gene that was responsible. Coleman joined Perry¿s group before leaving to set up his own group at the University of Cologne.
The paper in Nature Neuroscience describes how the collaborators, having identified the mutant gene, developed several lines of transgenic mice that contained it. All the mice had delayed Wallerian degeneration, and this was dose dependent, depending on the number of copies of the gene that had been inserted into their genomes.
¿It just so happened that the original mutation brought together two otherwise totally independent genes, which have independent roles and probably remain separate in every other mouse and every human,¿ Coleman said. ¿What we now need to do is to find out which of these two genes is responsible for the delayed Wallerian degeneration phenotype. Once we have done that, we can screen human populations for mutations in these genes and, if we find any, we can check whether they are more likely or less likely to have certain neurodegenerative diseases.¿ He plans to carry out these studies with collaborators at the University of Oxford.
More detective work will be needed, however, to find out exactly how the protein product of the mutant gene exerts its effect, because it occurs only in the nucleus of nerve cells and not in their axons. ¿The location of the protein was a big surprise. It suggests that it protects the axon indirectly, and implicates the existence of other genes which mediate this protective effect,¿ Coleman said.
The chimeric protein encoded by the mutant gene comprises an enzyme that catalyses the synthesis of a molecule called NAD+, and a very small fragment of a protein that is involved in the metabolism of a molecule called ubiquitin.
He and his colleagues now want to find out whether the mutant protein has an effect on a range of mouse models of human neurodegenerative diseases, including those for Alzheimer¿s disease and diabetic neuropathy.