How nerves harmed by disease or traumatic injury begin to die is the focus of new research.
The study unveils new targets for developing drugs to slow or halt peripheral neuropathies and devastating neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
Peripheral neuropathy damages nerves in the body’s extremities and can cause unceasing pain, itching, burning, stinging, and sensitivity to touch. The condition is commonly associated with diabetes or develops as a side effect of chemotherapy.
Nerve cells talk to each other by transmitting signals along communication cables called axons. Such signals underlie vital activities, such as thinking and memory, movement, and language.
The researchers showed they could prevent axons from dying, a finding that suggests therapies could be developed to counteract the withering away of nerve axons. As senior author Jeffrey Milbrandt, head of the genetics department at Washington University School of Medicine in St. Louis, comments:
“We have uncovered new details that let us piece together a major pathway involved in axon degeneration.
This is an important step forward and helps to identify new therapeutic targets. That we were able to block axon degeneration in the lab also gives us hope that drugs could be developed to treat patients suffering from a variety of neurological conditions.”
A commonality among many neurological disorders and traumatic nerve injuries is the degeneration of axons, which interrupts nerve signaling and prevents nerves from communicating with one another.
Axon degeneration is thought to be an initiating event in many of these disorders. In fact, an unhealthy axon is known to trigger its own death, and researchers are keenly interested in understanding how this happens.
Working in cell cultures, fruit flies, and mice, Milbrandt and coauthor Aaron DiAntonio, professor of developmental biology, and their colleagues showed that a protein already known to be involved in axon degeneration acts like a switch to trigger axon degeneration after an injury.
They found that when this protein is unleashed it causes a rapid decline in the energy supply within axons.
Within minutes after the protein, called SARM1, is activated in neurons, a massive loss of nicotinamide adenine dinucleotide (NAD), a chemical central to a cell’s energy production, occurs within the axon.
Said first author Josiah Gerdts, an MD/PhD student in Milbrandt’s laboratory:
“When a nerve is diseased or injured, SARM1 becomes more active, initiating a series of events that quickly causes an energetic catastrophe within the axon, and the axon undergoes self-destruction.”
Working in neurons in which SARM1 was activated, the researchers showed they could completely block axon degeneration and neuron cell death. This was done by supplementing the cells with a precursor to NAD, a chemical called nicotinamide riboside.
The neurons were able to use nicotinamide riboside to keep the axons energized and healthy.
Nicotinamide riboside has been linked in animal studies to good health and longevity.
But its benefits have not been shown in people. The researchers say much more research is needed to know whether the chemical could slow or halt axon degeneration in the body.
“We are encouraged by the findings and think that identifying a class of drugs that block SARM1 activity has therapeutic potential in neurological disorders,” Milbrandt says. “The molecular details this pathway provides give us a number of therapeutic avenues to attack.”
Gerdts et al
SARM1 activation triggers axon degeneration locally via NAD+ destruction
Science 24 April 2015: Vol. 348 no. 6233 pp. 453-457 DOI: 10.1126/science.1258366
Photo: Tom Deerinck and Mark Ellisman, National Center for Microscopy and Imaging Research (NCMIR) Myelinated axons in a rat spinal root.