Intra-axonal mechanisms driving axon regeneration

Brain Res, 2020 · DOI: 10.1016/j.brainres.2020.146864 · Published: August 1, 2020

Neurology Regenerative Medicine & Stem Cells

Simple Explanation

When axons are damaged, especially in the peripheral nervous system (PNS), they can sometimes regrow and reconnect. This process involves changes inside the axon itself, such as an increase in calcium levels. Axonal injury triggers signals that travel from the injury site back to the cell body (soma), prompting the neuron to switch from a maintenance mode to a growth mode. This involves changes in gene expression and protein synthesis within the axon. While similar signaling mechanisms exist in the central nervous system (CNS), they are not activated as effectively after injury, contributing to the limited regeneration capacity of CNS neurons compared to PNS neurons.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
Increased axoplasmic calcium is an early response to initiate regenerative growth programs, but excessive levels can trigger axon degeneration.
2
Axotomy alters axon-to-soma signals to initiate a neuronal regeneration program through retrograde transport of proteins and transcription factors.
3
Localized mRNAs in axons are subjected to post-transcriptional control, influencing protein synthesis and axon growth.

Research Summary

Axonal injury in the PNS invokes axon-to-soma and axon-to-nucleus signals through back-propagating wave of Ca2+ and retrograde transport of signaling proteins that change gene expression to support regeneration through transcriptional and epigenetic mechanisms. Part of the retrograde signaling is generated through localized synthesis Importin-β protein and transcription factors, whose intra-axonal translation is activated by increased axoplasmic Ca2+. Axon degeneration can also be triggered by increase in axoplasmic Ca2+, particularly by release from intracellular stores including the ER.

Practical Implications

Therapeutic Targets for Neural Repair

Understanding the intricacies of these mechanisms can be leveraged to develop effective therapies to improve neural repair in the PNS and CNS.

Dual-Function Therapies for Neuropathic Conditions

Therapies targeting some of these mechanisms may indeed provide dual functions for neuropathic conditions by supporting axon survival/integrity as well as encouraging axon branching for reinnervation of denervated target tissues.

Targeting axonal RNA transport/translation for neuropathies

A better understanding is needed for how broadly axonal RNA transport/translation or other axon-intrinsic mechanisms outlined above extend to inherited and acquired neuropathic conditions.

Study Limitations

1
More effort is needed to determine the intricacies of how these mechanisms support regeneration and how they are regulated.
2
A much better understanding is needed for how broadly axonal RNA transport/translation or other axon-intrinsic mechanisms extend to inherited and acquired neuropathic conditions.
3
The precise mechanisms by which non-neuronal cells and their secreted factors influence axonal injury responses and growth are not fully elucidated.

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