Decrease of mRNA Editing after Spinal Cord Injury is Caused by Down-regulation of ADAR2 that is Triggered by...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Spinal cord injury (SCI) is known to cause spasticity.
• Previous research indicated a decrease in serotonin receptor 2C (5-HT2CR) mRNA editing following SCI, correlating with spasticity.
• The precise molecular mechanisms underlying these changes remain to be fully elucidated.

Purpose of the Study:

• To investigate the impact of SCI on global mRNA editing and gene expression.
• To identify the molecular players responsible for altered mRNA editing after SCI.
• To understand how these molecular changes contribute to neurological dysfunction and spasticity post-SCI.

Main Methods:

• Massively parallel sequencing was employed to analyze mRNA editing and global gene expression profiles.
• Bayesian network analysis was utilized to model gene expression data.
• Specific gene targets, including 5-HT2CR and Kv1.1, were examined.

Main Results:

• SCI leads to a down-regulation of adenosine deaminase ADAR2, which is responsible for mRNA editing.
• Editing of both 5-HT2CR and the potassium channel Kv1.1 is reduced after SCI.
• Down-regulation of ADAR2 is triggered by SCI-induced persistent inflammation and microglial activation.
• Altered neuronal gene expression resulting from reduced ADAR2 activity contributes to neuronal hyperexcitability and muscle spasms.

Conclusions:

• Reduced ADAR2 expression and subsequent impaired mRNA editing are key mechanisms contributing to spasticity after SCI.
• Inflammatory responses post-SCI play a critical role in initiating these molecular changes.
• These findings offer potential therapeutic targets for treating spasticity and other central nervous system disorders.