Regulation of Autophagy by inhibitory CSPG interactions with Receptor PTPσ and its Impact on Plasticity and Regeneration after Spinal Cord Injury

Exp Neurol, 2020 · DOI: 10.1016/j.expneurol.2020.113276 · Published: June 1, 2020

Spinal Cord Injury Regenerative Medicine Genetics

Simple Explanation

Chondroitin sulfate proteoglycans (CSPGs) inhibit axon regeneration after CNS injuries by binding to Protein Tyrosine Phosphatase Sigma (PTPσ). This interaction dysregulates autophagy, a crucial cellular process. CSPGs/PTPσ interactions dampen autophagosome-lysosomal fusion at the axon growth cone, impairing the degradation of cellular materials. This dysregulation affects neuronal plasticity and regeneration, with implications for spinal cord injury and neurodegenerative diseases where CSPGs are upregulated.

Study Duration

Not specified

Participants

Rodent models of contusive SCI

Evidence Level

Not specified

Key Findings

1
CSPGs, particularly those with CS-E sulfation, bind with high affinity to PTPσ on axonal growth cones, disrupting autophagic flux by preventing autophagosome-lysosome fusion.
2
PTPσ activation by CSPGs dephosphorylates cortactin, an actin-binding protein essential for autophagosome-lysosome fusion, thereby inhibiting this process.
3
Modulating PTPσ with ISP (Intracellular Sigma Peptide) restores autophagic flux and converts dystrophic endings into normally migrating growth cones, suggesting a therapeutic avenue for promoting axon regeneration.

Research Summary

The review focuses on the role of chondroitin sulfate proteoglycans (CSPGs) and their interaction with the receptor protein tyrosine phosphatase sigma (PTPσ) in regulating autophagy following spinal cord injury (SCI). CSPGs, upregulated after CNS injuries, inhibit axon regeneration by disrupting autophagic flux at the growth cone through PTPσ. This dysregulation impacts neuronal plasticity and contributes to regeneration failure. Modulating the CSPG/PTPσ interaction may restore autophagic flux and promote axon regeneration, offering a potential therapeutic strategy for SCI and neurodegenerative diseases.

Practical Implications

Therapeutic target

PTPσ modulation, using agents like ISP, could alleviate CSPG-mediated inhibition of axon regeneration by restoring autophagic flux.

Understanding Disease Mechanisms

The CSPG/PTPσ/autophagy pathway offers insights into the mechanisms of axon regeneration failure in SCI and the roles of CSPGs in neurodegenerative diseases.

Enhancing Plasticity

Targeting CSPGs to modulate PTPσ signaling may enhance synaptic plasticity and functional recovery after CNS injuries.

Study Limitations

1
The precise intracellular binding partners of PTPσ that mediate axon inhibition or outgrowth are still largely unknown.
2
The effects of CSPG/PTPσ interactions on regulation of autophagic and lysosomal function in different cell types following injury need further characterization.
3
The specific mechanisms by which CSPGs and PTPσ contribute to the fine-tuning of synaptic plasticity across the lifespan of a synapse require further exploration.

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