Degeneration of axons, which transmit signals from one neuron to another, occurs in neurological diseases. A molecule called nicotinamide adenine dinucleotide (NAD+) has a crucial role in the maintenance of axons through unclear actions on a protein called Sarm1 that when activated can cause degeneration of neurons, the progressive atrophy and loss of function of neurons.

Recently, scientists from Peking University in Beijing, China, published an article in Nature where they found NAD+ binds to a region on human Sarm1 that inhibits its pro-neurodegenerative activity. Furthermore, disruption of the Sarm1 binding region to NAD+ activated the protein and led to axon degeneration in mouse neurons. These findings suggest a mechanism whereby NAD+ mediates the inhibition of Sarm1 in facilitating degeneration of neurons.

NAD+ is an essential molecule for making energy and maintaining health in cells. Levels of NAD+ in cells diminish with age, which scientists have linked to certain age-related neurodegenerative diseases, such as Alzheimer’s disease. How NAD+ levels in cells potentially influence degeneration of neurons has not been fully defined by researchers.

Activation of the Sarm1 protein promotes the molecular breakdown of NAD+, and its activation induces degeneration of neurons. It has three protein regions, also known as domains, known as ARM, TIR, and SAM, and the interactions between these domains influence the neurodegenerative activation of Sarm1.

In the study, the investigators used a technique for obtaining high resolution images of biological specimens called electron microscopy to look at the fine, molecular details of Sarm1. They found that the ARM domain interacts with the TIR domain and that NAD+ binding to the ARM domain inhibited the activity of the TIR domain along with Sarm1’s activity promoting the degeneration of neurons.

(Jiang et al., 2020 | Nature) An illustration of the three domains of Sarm1: the ARM, SAM, and TIR domains.

Mutations inhibiting the interaction between the ARM domain and the TIR domain induced extensive axonal degeneration. These results indicated that the ARM domain interacts with the TIR domain of Sarm1 to inhibit the neurodegenerative activity of Sarm1.

(Jiang et al., 2020 | Nature) Two mutations (W253A and F259A) in regions of the ARM domain of Sarm1 that disrupt its interaction with the TIR domain facilitate dramatic axonal degeneration.

Moreover, Sarm1 was activated by disrupting its NAD+ binding site as well as the interaction between the ARM and TIR domains, which led to axonal degeneration. These findings suggest that NAD+-mediated self-inhibition of Sarm1 causes degeneration of neurons.

(Jiang et al., 2020 | Nature) A mutation in the ARM domain of Sarm1 that disrupts NAD+ binding results in dramatic elevations in axon degeneration. The disruptive mutation, called RRK to E, resulted in significant axonal degeneration. The figure shows the drastic elevation in axonal degeneration associated with this mutation.

“Of particular interest, we discovered NAD+ as the novel ligand to Sarm1 ARM,” stated the investigators in their study. “The NAD+ binding could facilitate the protein’s self-inhibition, as the mutations impairing NAD+ binding produced the constitutively-active Sarm1. Notably, this NAD+-mediated self-inhibition mechanism is supported by a separate study,” they stated  in reference to the neurodegenerative-causing activities of Sarm1 with disrupted NAD+ binding. Importantly, these findings could also have clinical implications.

“The newly-revealed NAD+-binding site may become a promising drug target,” proposed the investigators. “Small-molecule analogs to NAD+ would block the Sarm1 activation…Such compounds could have broad implications for the treatment of different neurodegenerative diseases.”