Axon degeneration in nerve injury: a supposed brake turns out not to be one
In many neurodegenerative diseases, axons -- the long projections neurons use to transmit signals -- die off before the cell bodies themselves do. Scientists believed that death receptor 6, a protein on the cell surface, regulated this process. New experiments suggest that is probably wrong. A potential therapeutic target turns out to be no target at all.
Axon degeneration is a hallmark of diseases such as ALS, multiple sclerosis, Alzheimer's disease, and peripheral neuropathies. The loss of axons disrupts neuronal connections and typically precedes the death of the neuron itself, making it an early and therapeutically relevant process. Wallerian degeneration, in which axons degenerate after a nerve is severed, is the most widely used model for studying this mechanism.
A hypothesis that didn't hold up
Death receptor 6, also known as DR6 or TNFRSF21, had been placed on the list of candidate regulators of axon degeneration based on earlier research suggesting it activated signaling pathways that promote axonal breakdown. That made it an attractive potential therapeutic target: block the receptor, the thinking went, and you might slow axon loss in neurodegenerative diseases.
The new study, published in eLife, tested this hypothesis directly using the Wallerian degeneration model. The researchers found no evidence that DR6 regulates axon degeneration, nor that it influences how Schwann cells -- the support cells of the peripheral nervous system -- respond to nerve injury. In this context, the receptor simply does not appear to play any relevant role.
That is a disappointing result for anyone who had hoped for a new foothold for neuroprotective therapy. But negative results have real value in science: they stop research effort and investment from continuing to flow toward hypotheses that do not hold up. The mechanism of axon degeneration remains incompletely understood, and DR6 has simply been crossed off the list of suspects. The search goes on.