Findings suggest ways to block nerve cell damage in neurodegenerative diseases.
In many neurodegenerative conditions an early defect is the loss of axons, the wiring of the nervous system. When axons are lost, nerve cells can’t communicate as they should, and nervous system function is impaired.

In new research, scientists at Washington University School of Medicine in St. Louis have implicated a specific molecule in the self–destruction of axons. Understanding just how that damage occurs may help researchers find a way to halt it.

The study was published March 22 in the journal Neuron.

“Axons break down in a lot of neurodegenerative diseases,” said senior author Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. “Despite the fact these diseases have different causes, they are all likely rooted in the same pathway that triggers axon degeneration. If we could find a way to block the pathway, it could be beneficial for many different kinds of patients.” In previous studies, Stefanie Geisler, MD, an assistant professor of neurology, working with DiAntonio and Milbrandt, showed that blocking this axon self–destruction pathway prevented the development of peripheral neuropathy in mice treated with the chemotherapy agent vincristine. The hope is that if methods are developed to block this pathway in people, then it might be possible to slow or prevent the development of neuropathy in patients.

Toward that end, the Milbrandt and DiAntonio labs showed that a molecule called SARM1 is a central player in the self–destruct pathway of axons. In healthy neurons, SARM1 is present but inactive. For reasons that are unclear, injury or disease activate SARM1, which sets off a series of events that drains a key cellular fuel — called nicotinamide adenine dinucleotide (NAD) — and leads to destruction of the axon. Though the researchers previously had shown SARM1 was required for this chain of events to play out, the details of the process were unknown.

SARM1 and similar molecules — those containing what are called TIR domains — most often are studied in the context of immunity, where these domains serve as scaffolds. Essentially, TIR domains provide a haven for the assembly of molecules or proteins to perform their work.

The researchers had assumed that SARM1 acted as a scaffold to provide support for the work of destroying axons, beginning with the rapid loss of cellular fuel that occurs minutes after SARM1 becomes active. The scientists set about searching for the demolition crew — the active molecule or molecules that use the SARM1 scaffold to carry out the demolition. The study’s first author, Kow A. Essuman, a Howard Hughes Medical Institute Medical Research Fellow and an MD/PhD student in Milbrandt’s lab, performed a litany of cellular and biochemical experiments searching for the demolition crew and came up empty.

“We performed multiple experiments but could not identify molecules that are traditionally known to consume NAD,” Essuman said.

But as a last resort, the investigators tested SARM1 itself. To their great surprise, they found it was doing more than simply providing a passive platform. Specifically, the researchers showed SARM1’s TIR domain acts as an enzyme, a molecule that carries out biochemical reactions, in this case destroying axons by first burning all their NAD cellular fuel.