Inhibition of a tumor suppressor enzyme called MST1 could reverse the effects of the genetic mutations that cause Charcot-Marie-Tooth disease type 4J (CMT4J), researchers show in a fruit fly study.
The study, “Loss-of-function mutation in Hippo suppressed enlargement of lysosomes and neurodegeneration caused by dFIG4 knockdown,” was published in the journal NeuroReport.
CMT4J is a rare, severe form of the disease caused by mutations in the FIG4 gene. The role of this gene is not fully understood, but previous studies have suggested that it could be an important regulator in the normal cleaning system of cells. In the absence of functional FIG4 protein, cells are unable to get rid of their waste, leading to the accumulation of toxic material inside them.
These findings suggest that targeting the cell’s cleaning system mechanism, particularly direct partners of FIG4 in the process, could represent a therapeutic opportunity for CMT4J.
To address this hypothesis, Japanese researchers conducted a series of genetic experiments in fruit flies. They not only investigated the role of FIG4 in nerve cell degeneration, but also the contribution of the gene that provides instructions for the MST1 enzyme.
MST1 is best known for its activity as tumor suppressor. But it has also been reported to be involved in regulating the cell’s cleaning system, as well as the neurodegenerative process in Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).
Researchers found that the loss of the dFIG4 gene — the fly equivalent to human FIG4 — in just the flies’ eyes led to rough eye structures. When the team also mutated the Hippo gene — the fly equivalent of the gene responsible for MST1 — it reduced the defects in the eyes that had been triggered by dFIG4 loss.
“These results indicate that dFIG4 genetically interacts with Hippo,” the researchers wrote.
Next, the team analyzed the impact of these genetic alterations in nerve cells that control movement. They found that fly larvae lacking dFIG4 had motor nerve cells with shorter responsive terminals than larvae in the control group. In contrast, those that lacked just Hippo had similar nerve cells to controls. As in the previous result, loss of both genes at the same time partially reversed dFIG4‘s negative effect in motor nerve cells.
Evaluation of the larvae’s crawling ability further demonstrated these findings. Loss of dFIG4 significantly impaired their ability to move, both in distance and speed, while additional loss of Hippo allowed the larvae to fully recover their mobility.
These results suggest that Hippo can modify the effects of the CMT4J-causing gene, potentially representing an opportunity “for the development of disease-modifying therapy,” according to the researchers.
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