Amino-terminal proteolytic fragment of the axon growth inhibitor Nogo-A (Rtn4A) is upregulated by injury and promotes axon regeneration

J. Biol. Chem., 2023 · DOI: https://doi.org/10.1016/j.jbc.2023.105232 · Published: September 9, 2023

Regenerative Medicine Neurology Genetics

Simple Explanation

This study investigates how an amino-terminal fragment of Nogo-A, a protein known to inhibit axon growth, is produced and whether it affects axon regeneration after injury. The research shows that this Nogo-A fragment is created through proteolysis, a process that is enhanced after injury to the nervous system. This fragment promotes axon regeneration in laboratory settings. The study also identifies HSPA8 as a protein that interacts with the Nogo-A fragment and contributes to axon regeneration, suggesting a new pathway for promoting neural repair.

Study Duration

Not specified

Participants

Mice, cortical neurons, HEK293T cells

Evidence Level

Not specified

Key Findings

1
An amino-terminal fragment of Nogo-A (aa 1-213) is produced by proteolysis near G214-N215 and its levels are increased after axotomy.
2
This Nogo-A fragment promotes axon regeneration in vitro in a cell-autonomous manner, unlike the inhibitory extracellular action of other Nogo-A domains.
3
The amino-terminal Nogo-A fragment interacts with HSPA8, and suppression of HSPA8 expression decreases axon regeneration, while overexpression increases it.

Research Summary

The study identifies a growth-promoting amino-terminal fragment of Nogo-A that is released by proteolysis and upregulated after injury. This fragment promotes axon regeneration in vitro and interacts with HSPA8, a chaperone protein that also regulates axon regeneration. The findings provide a potential explanation for varied results in previous Nogo-A gene-targeted mouse studies and reveal a new target for promoting axon regeneration after CNS injury.

Practical Implications

Therapeutic Target

The amino-terminal Nogo-A fragment and its interaction with HSPA8 could be targeted to develop new therapies for promoting axon regeneration after CNS injuries.

Understanding Conflicting Results

The discovery helps explain why previous studies with Nogo-A gene-targeted mice showed conflicting results, as the presence or absence of this specific amino-terminal fragment can significantly impact axon regeneration.

Chaperone Activity

Enhancing HSPA8 chaperone activity could be a novel approach to increase axon extension and improve outcomes after spinal cord injury or other neurological traumas.

Study Limitations

1
The responsible protease(s) for Nogo-A cleavage near aa G214/N215 has(have) not been determined.
2
The precise cleaved peptide bond at G214/N215 was not determined precisely.
3
The study primarily focuses on in vitro experiments, and further in vivo studies are needed to validate the findings.

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