Targeting Ribosomal Proteins for Optic Nerve Repair

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Researchers at the University of Connecticut School of Medicine report that two ribosomal proteins associated with neurodevelopment and neurodegeneration—Rpl7 and Rpl7A—downregulate as the nervous system develops but can be altered to be expressed in adult nerve cells in a mouse model of optic nerve injury.

Their study, published in Experimental Neurology, goes on to describe that when bundles of retinal ganglion cells’ axons were crushed (to model damage to the optic nerve), the neurons that the researchers had altered—using viral vectors to overexpress Rpl7 or Rpl7A—began to grow axons again after injury.¹ In other words, experimentally enhancing the levels of Rpl7 or Rpl7A in retinal ganglion cells in a mouse model promoted regeneration of damaged nerve cell axons after injury, said lead investigator Ephraim F. Trakhtenberg, PhD.

“We believe that experimental treatments targeting ribosomal proteins could tilt the balance toward the necessary levels of reactivation of axon growth mechanisms,” said Dr. Trakhtenberg, noting that he and colleagues are continuing to work toward this goal.

OPTIC NERVE SECTIONS. An image from the study indicates optic nerve crush sites two weeks after nerve crush, including (left to right) proximal, medial, and distal views.

Rationale. Dr. Trakhtenberg’s team initially looked at a group of 80 ribosomal protein genes—all of which progressively become less active as nerve cells mature—but focused on Rpl7 and

Rpl7A because “Rpl7 was previously reported to be dysregulated in neurodegenerative diseases, and Rpl7A was selected as a control because of its relatedness to Rpl7,” Dr. Trakhtenberg said. The researchers hypothesized that experimentally upregulating Rpl7 and Rpl7A into injured cells would fully reinstate their embryonic levels of expression and promote axon regeneration.

Of mice and humans. The research is early, and animal studies do not necessarily equate to similar results in humans. Jeffrey L. Goldberg, MD, PhD, at the Byers Eye Institute at Stanford University, in Stanford, California, who was not involved in the study, said, “Although the distance between mice and humans is large, the shared biology is significant. And vision loss in traumatic, ischemic, glaucomatous, and other optic neuropathies in our patients has more similarities than differences.”

Looking ahead. More research is needed to explore the role of ribosomal proteins in the regeneration of other neuron types and to determine the mechanism by which Rpl7 and Rpl7A regulate axon regeneration and retinal ganglion cell survival, said Dr. Trakhtenberg. Researchers also need to assess whether regulation of multiple ribosomal subunits has an even greater impact on axon regeneration, he said, noting that the ultimate goal would be to study their findings in the human eye.

According to Dr. Goldberg, uncovering the molecular mechanisms that promote axon regeneration is critical for developing new therapies and has the potential to open up a whole new field of research into the role of ribosomal proteins, local protein translation, and cell signaling pathways with clinical impact. “With molecular or gene therapy, these data could be rapidly translatable to clinical testing,” he said.  

—Christos Evangelou, PhD

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1 Xing J et al. Exp Neurol. 2023;368:114510.

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Relevant financial disclosures: Dr. Goldberg—None. Dr. Trakhtenberg—None.

For full disclosures and the disclosure key, see below.

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