Neuronal damage comes from traumatic brain injuries and diseases of the brain, such as Alzheimer’s disease and Parkinson’s disease. The damage to neurons resulting from injuries and diseases can occur in the short-term immediately after the incidence or chronically in the long-term. Researchers use a variety of animal models for injury and disease in hopes of identifying therapeutic strategies for both short- and long-term neuronal damage.

Recently, Kim and colleagues from Hallym University in Korea published a review article in Biomolecules where they discussed the role of the molecule nicotinamide adenine dinucleotide (NAD+) and its precursors in neuronal damage of roundworms (C. elegans). They proposed that high levels of NAD+ can protect neurons from damage, while lowered levels of NAD+ can promote the generation of the region of neurons that relay cellular signals–the axon. They also looked at whether regulating NAD+ levels at specific time frames in different tissues can counter neurodegenerative diseases and neuronal damage from neural conditions and injuries.

NAD+ has a plethora of roles in cells, from use in metabolic reactions to generate energy for the body to cell signaling, DNA repair, and gene expression. Enzymes that synthesize or consume NAD+ have been shown to play key roles in protecting neurons and in axon regeneration. Since humans and roundworms share all of the molecular components that synthesize and regulate NAD+, researchers have used roundworms to study the effects of altering NAD+ levels in neurons.

Some of the recent findings from NAD+ research using roundworms presented in the review focused on how studies of short-term axon injury indicated that high levels of NAD+ do not protect against axon degeneration. Scientists have used roundworms with genetic mutations that increase the levels of NAD+ in neurons, which showed no protective role against the degeneration of axons from axonal injury induced with a microscopic laser.

Further research presented in the review involved examining long-term neuronal damage and found that elevated levels of NAD+ play a neuroprotective role, protecting the cell body. When scientists increased NAD+ levels by manipulating levels of an enzyme that has a key role in NAD+ biosynthesis, NMNAT/NMAT-2, they found the higher NAD+ levels had neuroprotective properties in roundworms with neuronal damage.

(Lee et al., 2020 | Biomolecules) Roundworm models of neuronal damage help to understand the cellular mechanisms by which manipulating NAD+ can contribute to therapeutics in neuronal damage. There are a variety of ways that neuronal damage can be modeled in roundworms. (A) Short-term axon injury can be induced by laser-assisted axon damage. (B) One way that long-term neuronal damage can be elicited with genetic manipulations that confer chemical overstimulation of neurons (excitotoxicity), with mutations facilitating neurodegenerative diseases, or chronic exposure to chemotherapeutic agents.

The review presented data indicating that a cellular mechanism whereby elevated NAD+ levels can inhibit axon regeneration involves proteins called PARPs that depend on NAD+ to function. Interestingly, mutant worms with inhibited PARP function had enhanced axon regeneration capabilities. Furthermore, the investigators speculated that decreased NAD+ levels with mutations in enzymes that synthesize NAD+ didn’t activate the inhibitory activity of PARP proteins on axon regeneration. Thus, according to their theory, reduced NAD+ levels would promote axon regeneration.

“As we come to understand NAD+ biology in greater detail, we may need to regulate the NAD+ levels in proper time frames and in specific tissues,” stated Kim and colleagues in their review. Following neuronal damage, treating with a high dose of NAD+ may help protect damaged neurons, and depleting NAD+ later may then help regenerate axons. A comprehensive understanding of NAD+ biology could lead to the development of NAD+ therapeutics for neuronal damage conditions.

(Lee et al., 2020 | Biomolecules) NAD+ levels and the responses of damaged neurons in roundworms indicate that elevating NAD+ levels during certain time frames promotes neuroprotection while depleting NAD+ levels during others stimulates axon regeneration. (A) Elevated levels of NAD+ protect damaged neurons, while lowered levels of NAD+ promote axon regeneration. (B) A proposed strategy of raising and lowering NAD+ levels at different time frames to improve recovery from neuronal damage.