Widely used to study several human diseases, zebrafish can now be a useful preclinical model to study amyotrophic lateral sclerosis (ALS) linked to angiogenin mutations, according to researchers at the University of Bath.
The model was described in a study, “The catalytic activity and secretion of zebrafish RNases are essential for their in vivo function in motor neurons and vasculature,” and published in the journal Scientific Reports.
Angiogenin is a stress-activated protein that is known to be involved in the development and protection of the central nervous system. It is present in the brain and spinal cord, and it helps protect motor nerve cells from dying.
Mutations in the angiogenin coding gene have been associated with lower neuroprotective activity and reduced cell proliferation, and have been found in patients with ALS.
Previous preclinical studies with a mouse model of ALS have shown that treatment with non-mutated angiogenin protein could increase motor nerve cell’s survival, delay motor dysfunction, and increase mice lifespan.
Zebrafish are commonly used as easy, simple models to explore the underlying biological mechanisms of human diseases, but they have some limitations, such as the inability to mimic all human disease.
Therefore, the University of Bath researchers used NCI-65828 and terrein to test if zebrafish could be used to study ALS. NCI-65828 is a small molecule that inhibits the enzymatic activity of human angiogenin, and terrein is fungal metabolite known to prevent the secretion of this protein.
They found that NCI-65828 was a potent inhibitor of zebrafish’s RNase-like proteins (or Rnasels), which are the fish version of human angiogenin. In general, three natural Rnasels were found to be mainly present in the spinal cord of zebrafish.
Treatment with either NCI-65828 or terrein led to significantly fewer motor nerve cells in the spinal cord of zebrafish embryos compared with untreated, normally developing embryos. Impaired activity of Rnasels also led to proliferation of abnormally structured motor nerve cells, which resulted in abnormal swimming behavior with features of paralysis.
Further analysis revealed that inhibition of these proteins would lead to changes in the blood vessel structures in developing zebrafish.
“The more we understand about ALS and the complex interplay of all the various molecules we know to be involved, the better we will understand it and the more chance we have of developing therapies,” Vasanta Subramanian, PhD, associate professor at The University of Bath and senior author of the study, said in a university news release.
“Therefore being able to model the disease in zebrafish is a really important and useful way to push our scientific knowledge forwards,” she added.
While zebrafish have previously been used to study the role of other genes implicated in ALS, such as SOD1 and C9orf72, this is the first study in zebrafish to evaluate the impact of ALS-associated human angiogenin variants.
In addition, the study showed that Rnasels mimic many of the features of human angiogenin, in contrast to what has been demonstrated in mouse models of ALS.
“Our research suggests the zebrafish is useful as a model to dissect the molecular consequences of the human angiogenin variants linked to ALS,” Subramanian stated.
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