Injuries to the peripheral nervous system (PNS) trigger adaptive (pro-regenerative) or maladaptive (lack of regeneration, pain) responses determined by the expression levels of certain genes, i.e. by an intrinsic growth program, which ultimately act on the cytoskeleton of axotomized neurons. Successful nerve regeneration requires a precise balance between stable and dynamic microtubules, similar to neuronal development. However, even after surgical repair, functional recovery is largely absent due to slow regeneration and insufficient reinnervation of the target muscles.
DNA methylation is the most frequently studied epigenetic modification of gene expression. Previous studies have shown that global methylation and demethylation processes are fundamental mechanisms promoting axon regeneration. Epigenetic regulators such as TET enzymes (ten-eleven translocation methylcytosine dioxygenases) and UHRF1 (ubiquitin-like containing PHD ring finger 1) therefore play an important role in peripheral nerve regeneration. TET3, for example, is upregulated in spinal ganglia after sciatic nerve injury and promotes the expression of regeneration-associated genes (so-called RAGs). In addition, UHRF1 improves the regenerative capacity of sensitive neurons through promoter methylation (gene silencing) of PTEN and REST, which were already presented in an earlier blog post.
In addition to DNA methylation, histone modifications play a key role as classical epigenetic mechanisms of axonal regeneration. Histone deacetylases (HDACs) catalyze not only the deacetylation of histones in the nucleus, but also of proteins such as α-tubulin in the cytoplasm. Such post-translational modifications, such as the acetylation of tubulin, are crucially involved in axon regeneration, as the inhibition of microtubule dynamics reduces axon growth (stable and dynamic microtubules differ in the extent of tubulin acetylation). Following peripheral nerve damage, microtubules are remodeled to facilitate growth cone formation and promote axon regeneration.
The beneficial effects of low-dose ionizing radiation (LDIR) on this process have been known for decades. LDIR can induce adaptive responses that improve growth and functional capacity. For example, localized, low-dose X-ray irradiation promotes nerve repair and functional recovery in rats, although the mechanisms are not yet fully understood. Studies suggest that LDIR contributes to these adaptive effects via changes in DNA methylation and transcriptional profiles.
A study published in Neuron at the end of 2023 has now shown that two ionizing radiation sources, alpha particles and X-rays, promote axon growth in cultured peripheral nerve cells. Low-dose whole-body X-ray irradiation improves the intrinsic growth capacity of injured neurons and accelerates axon regeneration and functional recovery after sciatic nerve injury. Through genome-wide analysis of CpG methylation in these animals, the authors identified hypermethylation of the Fmn2 promoter as the main factor associated with the promoting effects of LDIR. The knockdown experiments of Fmn2 showed that its inhibition increases microtubule dynamics in growth cones and promotes axon regeneration. In addition, metaxalone was identified as an FDA-approved molecule that supports axon regeneration in vitro and in vivo. These results therefore offer a new approach for a potentially safe and effective pharmacologic therapy for peripheral nerve damage.
Reference:
Au NPB, Wu T, Chen X, Gao F, Li YTY, Tam WY, Yu KN, Geschwind DH, Coppola G, Wang X, Ma CHE (2023) Genome-wide study reveals novel roles for formin-2 in axon regeneration as a microtubule dynamics regulator and therapeutic target for nerve repair. Neuron 111:3970-3987.e3978
Image credit: iStock/Aldona
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