In a study that could open new approaches to neurodegenerative medicine, researchers identified tubulin polymerization promoting protein family member 3 as a promising molecular target for promoting optic nerve regeneration and protecting retinal ganglion cells.

Unlike peripheral nerves, mammalian central nervous system CNS axons, such as those in the optic nerve, have a limited capacity for regeneration following injury. This inability to regenerate impacts patients with conditions such as glaucoma or optic neuropathies, where retinal ganglion cell (RGC)damage results in irreversible vision loss.

In their study published in Acta Neuropathologica Communications, the researchers highlighted tubulin polymerization promoting protein family member 3 (Tppp3) as a novel marker and therapeutic target for RGCs. Through single-cell RNA sequencing, they identified that Tppp3 is expressed in RGCs across multiple species, including mice, macaques, and humans. Further experiments demonstrated that overexpression of Tppp3 in a rodent optic nerve crush (ONC) model significantly enhanced axon regeneration and improved RGC survival rates.

In vitro analyses showed that Tppp3 promotes neurite outgrowth, while in vivo studies showed its ability to regenerate axons over short distances and reduce RGC death post-injury.

The molecular mechanisms underlying Tppp3’s regenerative effects appear multifaceted. Bulk RNA sequencing indicated that Tppp3 upregulates pro-regenerative genes such as Bmp4 and alters inflammatory pathways, both of which play crucial roles in axonal repair. Additionally, Tppp3 stabilizes microtubules—critical cellular structures for axon growth and regeneration.

The researchers also found that Tppp3 might interact with the BMP signaling pathway, known for enhancing axon regeneration and neuronal survival. However, further research is needed to determine whether this occurs through canonical or alternative pathways, they noted.

Future studies in this area should look at how Tppp3-based therapies can be translated to human patients. Additionally, while this study showed that Tppp3 promotes short-distance axon regeneration, achieving long-distance regeneration with functional connectivity is essential for meaningful recovery, the researchers noted. Long-term safety studies are also critical, as Tppp3 has been implicated in cancer cell proliferation in other contexts. Future studies should also focus on optimizing delivery methods, understanding its long-term effects, and exploring synergistic treatments to maximize its regenerative capacity.

The authors noted competing interests in the published study.