PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure

The EMBO Journal, 2019 · DOI: 10.15252/embj.2018101032 · Published: May 22, 2019

Regenerative Medicine Neurology Genetics

Simple Explanation

Following a central nervous system (CNS) injury, such as stroke or spinal cord injury, axonal regeneration is highly restricted. In stark contrast, spontaneous albeit partial functional axonal regeneration is possible after a peripheral nervous system (PNS) injury. The peripheral branch of DRG mounts a robust regenerative response following a sciatic nerve injury, while the central branch fails to regenerate following a spinal injury

Study Duration

Not specified

Participants

Adult mice (C57Bl6/J)

Evidence Level

Not specified

Key Findings

1
HDAC3 inhibition promoted neurite outgrowth on both growth-permissive and inhibitory substrates.
2
A regeneration-competent sciatic nerve injury induces an increase in calcium that activates protein phosphatase 4 (PP4) and slightly increases the activity of protein phosphatase 2 (PP2), which in turn dephosphorylate HDAC3, inhibiting its activity.
3
Genetic or pharmacological HDAC3 inhibition overcomes regenerative failure by promoting axonal growth of sensory axons following spinal cord injury.

Research Summary

The molecular mechanisms discriminating between regenerative failure and success remain elusive. We found that calcium increases in DRG following a regeneration-competent sciatic but not a regeneration-incompetent spinal injury to activate PP4c that is required for HDAC3 dephosphorylation. Our data propose calcium-dependent activation of PP4c and to a lesser extent of PP2a leading to dephosphorylation of HDAC3 as a novel molecular mechanism that discriminates between axonal regeneration versus regenerative failure in DRG sensory neurons.

Practical Implications

Therapeutic Target

HDAC3 inhibition may be a viable therapeutic strategy for promoting axonal regeneration after spinal cord injury.

Calcium Signaling

Enhancing calcium signaling in DRG neurons after spinal cord injury could promote PP4 activation and HDAC3 dephosphorylation.

Epigenetic Regulation

Targeting specific epigenetic mechanisms, such as HDAC3 activity, may offer a more effective approach for promoting axonal regeneration compared to broad-spectrum HDAC inhibitors.

Study Limitations

1
The study primarily focuses on DRG sensory neurons, and the findings may not be directly applicable to other neuronal populations or CNS regions.
2
The study identifies a novel molecular mechanism, but further research is needed to fully elucidate the downstream signaling pathways and transcriptional targets regulated by HDAC3.
3
The long-term effects of HDAC3 inhibition on axonal regeneration and functional recovery require further investigation.

Your Feedback

Was this summary helpful?

Back to Regenerative Medicine