Published online on June 7 in Science, their study, “dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway,” presents the first gene required for the active self-destruction of nerves following injury.
“If we can suppress this gene in humans after nerve or spinal cord injuries, we may be able to protect the nerve tissue from further harm,” said Stephan Züchner, M.D., associate professor of human genetics and neurology and director of the Center for Human Molecular Genetics at the Miller School’s John P. Hussman Institute for Human Genomics. “In addition, this gene could be a valuable therapeutic target for slowly progressing diseases of peripheral nerves, such as Charcot-Marie-Tooth disease.”
In the past, researchers used a mutant mouse model to study Wallerian degeneration (WLD), which results when a nerve fiber is damaged, and the part of the axon separated from the neuron degenerates. This mouse model delays Wallerian degeneration, but has several shortcomings, the most important being that this effect results from a serendipitous gene fusion – the WLDS gene – and not a naturally occurring protein. For the current study, a team led by Marc Freeman, Ph.D., associate professor of neurobiology at the University of Massachusetts Medical School, set out to use fruit flies to systematically identify natural genes that would mimic the effects of WLDS.
After Freeman’s team identified strains of fruit flies where the peripheral nerve loss was largely prevented after nerve severance, they aimed to find the gene responsible. Instead of lengthy gene mapping by traditional methods, they decided to team up with Züchner to apply the latest genomic technology – whole genome sequencing of the fruit flies. A neurologist and molecular biologist, Züchner has extensive experience in the mapping of Mendelian diseases and cloning of causal genes.
Züchner’s team identified deleterious mutations in dSarm/Sarm1, the gene responsible for nerve degeneration after injury, marking the first time that whole genome sequencing of flies was used to identify a novel disease gene.
Once the dSarm/Sarm1 gene was identified, the group of international experts created a mouse model that lacked this gene, which resulted in the same effect: the mouse nerves were protected after injury. The finding has enormous consequences for the understanding of nerve injury, and for the search for therapeutic interventions, Züchner said.
The study is the result of a collaborative effort with investigators from eight universities and research institutions in the U.S. and the United Kingdom. The senior investigators on Freeman’s team included Michael Coleman, Ph.D., of the Babraham Institute, Cambridge, U.K.; Marc Tessier-Lavigne, Ph.D., president of The Rockefeller University in New York and head of the Laboratory of Brain Development and Repair; and UM’s Züchner.