RNA Molecule Can Regulate Common Pathway of CMT and ALS, Fruit Fly Study Suggests
Conducted by researchers from the Kyoto Institute of Technology and collaborators at the Kyoto Prefectural University of Medicine in Japan, the study suggests that long-noncoding RNA molecules are involved in the regulation of a pathway that is activated in both CMT type 4J (CMT4J) and ALS.
The study, “Genetic screening of the genes interacting with Drosophila FIG4 identified a novel link between CMT-causing gene and long noncoding RNAs,” appeared in the journal Experimental Neurology.
CMT is a genetic disease characterized by motor and sensory impairment due to progressive peripheral nerve damage.
Several genes have been associated with this disease, including FIG4, which is known to cause CMT4J. But mutations in this gene have also been associated with other disorders such as ALS and Yunis-Varon syndrome.
Despite its recognized disease-promoting role, little is known about the molecular mechanisms triggered by FIG4 mutations.
Researchers used genetically manipulated fruit flies lacking the FIG4 gene to explore changes in the genetic landscape that could shed light on FIG4-mediated mechanisms.
Fruit flies with reduced levels of FIG4 have what the researchers called “rough eye,” which is characterized by abnormally shaped eyes with impaired visual capacity. By taking advantage of this easily detectable manifestation of FIG4 loss, it is possible to identify potential activators or inhibitors of FIG4.
The team found that deletion of nine different chromosome regions led to suppression of rough eye manifestation, and deletion of 15 other chromosome regions caused the enhancement of rough eye.
Notably, deletion of one particular region that suppressed rough eye had been previously shown to have a similar effect in a fly model of ALS. The region in question encoded a total of 28 genes.
With several additional experiments, the researchers were able to narrow the list of genes of interest to just four that could effectively suppress the rough eye manifestation, and three genes that could enhance the damaging effect of low FIG4 levels.
“Human homologues [equivalent genes] of some of these genes may play roles in CMT [development],” the researchers said.
Among the four suppressing genes was CR18854, which is known to provide instructions for the production of a long-noncoding RNA molecule. Although long-noncoding RNA molecules are generally not directly implicated in human disease, they have an important regulatory role over other genes.
Flies that lacked FIG4 in nerve cells showed impaired motor capacity and reduced mobility, whereas those that had both FIG4 and CR18854 mutated showed improved motor skills. These results demonstrated that “mutation and knockdown of CR18854 could effectively rescue the locomotive defect” promoted by neuron-specific FIG4 loss, according to the researchers.
When the team repeated these experiments in flies with genetically induced ALS, they saw similar results. Loss of CR18854 effectively prevented the damaging effects of mutant Caz gene — the fly version of the ALS-causing FUS gene.
Supported by these findings, the team believes that some long-noncoding RNAs such as CR18854 could regulate a “common pathway” involved “in CMT and ALS [development].”