Specific mRNA molecule may be useful as biomarker in ALS
Molecule found to be not edited as efficiently in ALS patients: Study
A messenger RNA (mRNA) molecule that provides the instructions for a protein involved in glutamate signaling is not edited as efficiently in amyotrophic lateral sclerosis (ALS) patients as in people without the neurological disorder, according to a new study suggesting its potential use as an ALS biomarker.
Glutamate is required for the proper communication between nerve cells — but its signaling is believed to be disrupted and contribute to disease progression in people with ALS.
The efficiency with which the mRNA molecule gets edited may be a useful marker to help detect and measure the severity of ALS, the findings suggested.
The study, “Glutamine/arginine site-unedited GluA2 mRNA in cerebrospinal fluid as a biomarker for amyotrophic lateral sclerosis,” was published in the Journal of Neurology, Neurosurgery and Psychiatry.
Testing editing efficiency of an mRNA molecule
Most cases of ALS are sporadic, meaning they occur in people with no family history of the disease. ALS is diagnosed based on the symptoms a patient is experiencing; there are, as of now, no reliable biomarkers that can be objectively measured to detect ALS or to measure the disease’s progression.
Now, scientists in Japan tested whether a specific mRNA molecule might be a viable biomarker of ALS.
mRNA is an intermediary molecule that’s produced when genes are used, or read, to make proteins. The genetic code is transcribed from a cell’s DNA into a temporary mRNA molecule, which is then shipped to the cell’s protein-making machines and used as a template to make a protein.
While the causes of sporadic ALS remain poorly understood, prior research has suggested that mRNA processing becomes dysregulated, or impaired, in ALS.
This new study specifically focused on the mRNA molecule that carries instructions for making a protein called GluA2. The GluA2 protein helps to form a receptor that nerve cells use to detect a signaling molecule called glutamate. Abnormal glutamate signaling can have toxic effects on nerve cells and has been implicated in ALS.
Under normal circumstances, the mRNA undergoes a process of molecular editing at a specific location, dubbed the glutamine/arginine or Q/R site, before it is used to produce GluA2 protein. Previous research has suggested that this molecular editing may be less efficient in nerve cells impacted by ALS.
To find out, the researchers here measured the percentage of GluA2 mRNA with editing at the Q/R site in 24 people with ALS. Similar data was culled for 23 people with other neurological disorders but not ALS. Samples of cerebrospinal fluid or CSF, the liquid that surrounds the brain and spinal cord, were used for the analysis.
The results showed that the average percentage of properly edited mRNA molecules was significantly lower among the ALS patients. In fact, among the individuals who did not have ALS, the lowest detected editing efficiency was about 94.8%. By comparison, 13 of the 24 ALS patients had a percentage at or below 94.65%; a few individual patients had an efficiency lower than 80%.
Editing efficiency of [less than] 94.65% may be an indicator of sporadic ALS.
“Editing efficiency at the Q/R site of CSF GluA2 mRNA was specifically reduced in patients with ALS [relative to] that in patients without ALS, whose editing efficiency was 94.8% at the lowest,” the researchers wrote.
“Accordingly, editing efficiency of [less than] 94.65% may be an indicator of sporadic ALS,” they wrote.
Among the ALS patients, the 13 with a lower percentage of properly edited mRNA molecules tended to have been living with ALS for longer, and they generally had more severe physical impairment. This was reflected by lower scores on the the ALS Functional Rating Scale–Revised (ALSFRS-R) and its subscales.
Collectively, these data suggest that “the editing efficiency of CSF GluA2 mRNA is a potential biomarker for diagnosis, disease progression and treatment efficacy in sporadic ALS,” the researchers concluded.
Among the study’s limitations was its small size, the researchers noted. Thus, further work will be needed to validate these results and assess the potential utility of measuring this type of mRNA editing biomarker in clinical practice.
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