Despite its well-known role in inflammation, the microRNA molecule known as miR-155 does not seem to be a promising target for the treatment of Gaucher disease, as its inactivation failed to counteract the shorter lifespan and robust inflammatory state seen in zebrafish models of the condition, a study reports.
The study, “Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher’s disease,” was published in the journal Neurobiology of Disease.
Gaucher disease is a rare lysosomal storage disorder, caused by mutations in the GBA gene, which result in a deficiency of the glucocerebrosidase enzyme. As a consequence, a type of fat called glucocerebroside cannot be properly broken down and accumulates inside cells in certain organs, leading to a generalized inflammatory status.
One of the key hallmarks of Gaucher is neurodegeneration (deterioration of brain cells), and researchers point to neuroinflammation as a major contributing factor.
Aiming to learn more about Gaucher disease, a group of researchers at the Sheffield Institute for Translational Neuroscience previously developed a zebrafish model that captured key aspects of the human Gaucher disease, including inflammation, neurodegeneration, and high levels of Gaucher biomarkers.
Using the zebrafish model, the researchers reported an increase in levels of a type of microRNA molecule known as miR-155. MicroRNAs are small molecules that regulate gene expression.
Interestingly, other studies have indicated that miR-155 is a master regulator of inflammation, and its role has been implicated in a wide range of other neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases.
Furthermore, researchers noticed that an elevation in miR-155 levels actually precedes the development of widespread disease and neuroinflammation in the zebrafish model, indicating that it likely plays a role in disease initiation and/or progression.
In this study, the researchers looked at mammalian model systems of the disease to investigate whether a rise in miR-155 levels is a universal feature of Gaucher. They also wanted to find out whether depletion of miR-155 would have a neuroprotective effect on the zebrafish model of the condition.
In fact, miR-155 was found to be highly expressed in mammalian models of Gaucher, confirming that miR-155 elevation is a shared feature across different species with the condition.
Next, the researchers used a technique known as CRISPR/Cas9 to develop a zebrafish line lacking miR-155 expression. CRISPR/Cas9 is a highly specific gene-editing technique, commonly used by researchers to induce mutations in specific gene.
They hypothesized that deleting the miR-155 gene would increase the lifespan of and reduce neuroinflammation in their zebra fish model. Unexpectedly, however, they found that loss of miR-155 did not increase the lifespan or reduced the inflammatory markers of Gaucher disease. Instead, brain inflammation appeared to increase by 40% in these animals.
These findings show “that neither neuroinflammation nor disease progression in [glucocerebrosidase] deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic target in Gaucher’s disease,” the researchers concluded.