Mutations in the C9orf72 gene deregulate the process by which cells remove waste, leading to a buildup of toxic elements inside them, researchers have found.
This discovery expands knowledge on how C9orf72 may contribute to the development and progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
The study, “A C9orf72 ALS/FTD Ortholog Acts in Endolysosomal Degradation and Lysosomal Homeostasis,” was published in the journal Current Biology.
Several genes have been linked to the inherited form of ALS, but in up to 40 percent of cases, the C9orf72 gene is mutated. The role of this gene in cells and its contribution to ALS is not yet fully understood.
To shed light on this matter, researchers at the Massachusetts Institute of Technology studied the alfa-1 gene in Caenorhabditis elegans worms, which is the equivalent gene to C9orf72 in humans.
The team genetically engineered worms to lack functional alfa-1, similar to what happens in human disease. This led to clear alterations during the early embryonic development of the worms, with the accumulation of small “blobs” floating in the fluid surrounding the embryos.
Additional experiments confirmed that mutations in alfa-1 impaired the mechanism cells use to get rid of their waste, and the “blobs” resulted from the accumulation of unwanted, toxic products of cell activity.
In the case of C. elegans worm embryos, this defect resulted in reduced absorption of nutrients, which directly impacted their ability to survive. And those that did survive appeared to develop later than normal.
Next, the researchers introduced the human C9orf72 gene in these defective embryos. This approach partially reversed the “blob” effect, suggesting that alfa-1 and C9orf72 have similar functions.
Transposing this information into human disease, this could mean that loss of C9orf72 in brain cells might lead to an impaired waste cleaning process in cells and, consequently, the accumulation of toxic products. Such effects are actually consistent with some of the classical features of ALS, including increased inflammation.
Still, additional studies are needed to further dissect the role of C9orf72 in human cells, and to confirm if its loss could lead to a similar outcome as that of alfa-1 in worms.
“If you cannot degrade things properly in cells that live for very long periods of time, like neurons, that might well affect the survival of the cells and lead to disease,” Anna Corrionero, PhD, lead author of the study, said in an MIT news story.
Several pharmaceutical companies are currently developing therapies engineered to block the production of the mutant C9orf72. In light of these new findings, this could potentially lead to some adverse effects that researchers should watch for.
“In developing any drug, you have to be careful to watch for possible side effects. Our observations suggest some things to look for in studying drugs that inhibit C9orf72 in ALS/FTD patients,” Corrionero said.