Restoring a protein that’s missing in a type of ALS that affects 10 percent of patients stopped nerve cell deterioration, University of Southern California researchers report.
The results also applied to a disease called frontotemporal dementia, or FTD, according to the team at USC Stem Cell.
Their study, ”Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons,“ appeared in Nature Medicine.
ALS affects about four Americans in 100,000 — or 13,300 people, according to estimates. FTD is the second most common cause of degenerative dementia after Alzheimer’s, representing 10-20 percent of all dementia cases.
Some signs of FTD can also be seen in ALS patients — a reflection of the disorders sharing genetic mechanisms. One of the shared mechanisms is mutations of the C9ORF72 gene, which are responsible for a tenth of both ALS and FTD cases.
A common feature of the disorders is an accumulation of protein clumps in nerve cells.
In the central nervous system, C9orf72 protein is involved in the autophagy pathway, a route that cells use to get rid of potentially toxic material.
C9ORF72 gene mutations lead to the generation of neurotoxins that scientists have targeted in attempts to develop treatments for neurodegenerative disorders. These strategies have yet to stop the degeneration of patients’ nerve cells in a lab, however.
The USC team wanted to learn more about the C9orf72 protein’s role in ALS and FTD.
One step was to genetically engineer blood from ALS patients carrying the C9ORF72 mutation to create the movement nerve cells the disease affects. In addition, they took blood from healthy volunteers, reprogrammed blood cells to become movement nerve cells and used gene editing to delete the C9ORF72 gene.
A key finding was that lower amounts of C9orf72 protein in the movement nerve cells of both ALS patients and healthy people with a deleted C9ORF72 gene mutation.
Importantly, restoring C9orf72 levels or augmenting the protein’s function led to nerve cell survival and stopped neurodegenerative processes in mouse models. “Increasing C9orf72 activity in motor neurons [nerve cells] should mitigate disease and provides a new therapeutic target,” the researchers wrote.
The study also demonstrated that movement nerve cells use C9orf72 protein to build lysosomes —structures that help clean cells of toxic waste.
The team is now using movement nerve cells from patients to test multiple treatment candidates, focusing on those that target lysosomes.
“By understanding the role of lysosomes in ALS and [FTD], we can better target our search for new drugs or therapies to treat these devastating diseases,” Dr. Justin K. Ichida, the study’s senior author, said in a press release.