Dysregulated glutamatergic signaling and RNA editing in the pathogenesis of ALS

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Assessing the effectiveness of GluA2 mRNA editing in CSF can provide valuable insight into the diagnosis and prognosis of ALS, as well as guide the development of potential therapeutic approaches, a new study from Tokyo Medical University suggests. enter image description here The disease known as ALS is multifaceted, in fact not only are there believed to be dozens of ALS subtypes, but there are also dozens of diseases that have similar symptoms to ALS. This greatly complicates not only the diagnosis, which is always long and uncertain, but also the clinical trials which are based on the implicit assumption that all the patients treated have the same disease, which is probably not the case for the trials of drugs for degenerative diseases.

The publication by researchers at the University of Tsukuba that interests us today discusses the need for reliable diagnostic biomarkers and treatment predictors for amyotrophic lateral sclerosis. The authors highlight the role of dysregulated glutamatergic signaling and RNA editing in the pathogenesis of ALS. They focus specifically on the glutamine/arginine (Q/R) site of the mRNA of GluA2, a subunit of AMPA receptors, which is normally edited by RNA-acting adenosine deaminase 2 (ADAR2) in healthy neurons. In sporadic ALS, downregulation of ADAR2 leads to expression of unedited GluA2 mRNA at the Q/R site, resulting in motor neuron death.

Researchers at the University of Tsukuba studied the mRNA editing efficiency of GluA2 in the cerebrospinal fluid (CSF) of patients with sporadic ALS and compared it to non-ALS controls. They found a significant reduction in the editing efficiency at the Q/R site of GluA2 mRNA in the CSF of ALS patients, suggesting that it could serve as a diagnostic biomarker for ALS. They also observed a correlation between reduced editing efficiency and clinical parameters such as longer disease duration and more advanced symptoms, particularly affecting the lower extremities.

GluA2 mRNA is an RNA molecule that contains instructions for the production of the protein GluA2, which is a subunit of AMPA receptors, glutamate receptors.

Editing efficiency refers to the extent to which the Q/R site of GluA2 mRNA is modified by the enzyme ADAR2. In healthy neurons, ADAR2 edits GluA2 mRNA at the Q/R site, converting adenosine to inosine. However, in sporadic ALS, ADAR2 is downregulated, resulting in unedited GluA2 mRNA expression at the Q/R site. This decrease in editing efficiency suggests impaired GluA2 mRNA regulation in sporadic ALS.

Specifically, ALS patients with reduced editing efficiency experienced longer disease duration and more advanced symptoms, including impaired lower limb functions. These results suggest that GluA2 mRNA editing efficiency in CSF may be associated with the progression and severity of sporadic ALS.

The study implies that the efficiency of editing at the Q/R site of GluA2 mRNA could not only help diagnose ALS, but also help identify treatable ALS cases. Therapies targeting dysregulation of RNA editing are currently being developed, and this biomarker could potentially help predict treatment efficacy.

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