Nfe2l3 emerges as a possible neuroprotective candidate and therapeutic target in central nervous system injury/disease

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First authors Agnieszka Lukomska, PhD, and Matthew Frost, PhD, and colleagues reported that nuclear factor erythroid 2-like 3 (Nfe2l3) is a neuroprotectant and may have therapeutic potential for treating central nervous system (CNS) injury and disease.¹ The researchers are from the Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT.

They explained that Nfe2l gene family members -1, -2, and -3 mediate the cellular response to oxidative stress, including in the CNS. However, because the neuronal functions of Nfe2l3 remain undetermined, the team compared the expression levels of the 3 family members in single-cell RNA-seq (scRNA-seq)-profiled cortical and retinal ganglion cell (RGC) CNS projection neurons, they explained. Their goal was to determine if Nfe2l3 regulates neuroprotection and axon regeneration after a CNS injury in vivo.

They found that Nfe2l3 transiently peaked in developing immature cortical and RGC projection neurons, but in adult neurons the expression was nearly abolished and was not up-regulated after the injury.

They also reported that in the retina, Nfe2l3 is enriched in the RGCs, primarily neonatally, and was not up-regulated in injured RGCs, which was in contrast to the other 2 family members, Nfe2l1 and Nfe2l2, whose expression levels were robust in other retinal cell types and were up-regulated in injured RGCs.

In addition, the authors reported that intraocular viral vector delivery Nfe2l3 was expressed in injured RGCs and promoted neuroprotection and long-distance axon regeneration after the optic nerve injury in vivo.

The investigators said, “Nfe2l3 provided a similar extent of neuroprotection and axon regeneration as viral vector-targeting of Pten and Klf9, which are prominent regulators of neuroprotection and long-distance axon regeneration.”

They explained that when they bioinformatically characterized a gene network associated with Nfe2l3 in neurons, the association of Nfe2l3 was predicted with established mechanisms of neuroprotection and axon regeneration.

The conclusion reached was that “Nfe2l3 is a novel neuroprotection and axon regeneration-promoting factor with a therapeutic potential for treating CNS injury and disease.”

The take-home points from this study are as follows:

• Neuronal Nfe2l3 has a novel role in promoting neuroprotection and long-distance axonal regeneration after a CNS injury in vivo.
• Adeno-associated virus 2 expression of Nfe2l3 in adult RGCs provides similar neuroprotection and axon regeneration as shRNA KD of Pten or Klf9.
• Nfe2l3 is not meaningfully expressed in the adult RGCs before or after optic nerve injury.

Reference:

1. Lukomska A, Frost MP, Theune WC, et al. Nfe2l3 promotes neuroprotection and long-distance axon regeneration after injury in vivo. Exp Neurol. 2024;375:114741; https://doi.org/10.1016/j.expneurol.2024.114741