Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

Scientific Reports, 2021 · DOI: 10.1038/s41598-020-79624-0 · Published: January 11, 2021

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This study investigates the response of sensory neurons to spinal cord injury (SCI) compared to sciatic nerve injury (SNI). Using RNA sequencing, the researchers found that SCI elicits a different transcriptional response in dorsal root ganglion (DRG) neurons compared to SNI. Unlike SNI, the SCI response is not sustained, and it involves the downregulation of genes related to lipid metabolism. Inhibiting fatty acid synthase, an enzyme involved in lipid production, decreased axon growth in vitro. The findings suggest that decreased lipid metabolism after SCI may limit the regenerative capacity of axons.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
SCI induces a unique transcriptional response in DRG sensory neurons compared to peripheral nerve injury (SNI), with fewer differentially expressed genes and little overlap between conditions.
2
SCI leads to the downregulation of lipid biosynthesis-related genes in ascending DRG sensory neurons, potentially inhibiting axon growth. Pharmacologic inhibition of FASN, decreases axon growth and regeneration in vitro.
3
The upregulation of ATF3 and Jun after SCI is not sufficient to promote axon growth in vitro, suggesting other SCI-induced transcriptional changes may repress their pro-growth effects.

Research Summary

The study reveals that ascending DRG sensory neurons respond to SCI and alter their transcriptome differently than after SNI. SCI induces a stress response, marked by ATF3 and Jun upregulation, but this response doesn't promote a growth state, possibly due to ATF3 regulating genes that inhibit growth in the SCI context. Downregulation of lipid biosynthesis genes, particularly FASN, is identified as a potential mechanism inhibiting axon growth after SCI, as FASN inhibition decreases axon growth in vitro.

Practical Implications

Therapeutic Targeting of Lipid Metabolism

Modulating lipid metabolism-related genes, particularly FASN, could be a potential therapeutic strategy to enhance axon regeneration after SCI.

Combination Therapies with RATFs

Combining ATF3/Jun overexpression with interventions that counteract the downregulation of lipid metabolism could improve axon regeneration outcomes.

Temporal Dynamics of Transcriptional Responses

Understanding the temporal dynamics of the SCI response is crucial, as the study shows the response is not sustained over time. Therapies need to consider this to maintain a pro-regenerative environment.

Study Limitations

1
The study primarily focuses on transcriptional changes and in vitro experiments; in vivo validation is needed.
2
The mechanism by which decreased FASN expression impacts protein palmitoylation and axonal transport of SCG10 requires further investigation.
3
Differences in methodology between whole DRG and FACS-seq may influence the results.

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