CHICAGO, Dec. 13 (Xinhua) -- An international team of researchers has found that a lone mutation in a single gene that causes an inherited form of frontotemporal dementia makes it harder for neurons in the brain to communicate with one another, leading to neurodegeneration.
Unlike the more common Alzheimer's disease, frontotemporal dementia tends to afflict young people. It accounts for an estimated 20 percent of all cases of early-onset dementia.
Patients with the illness typically begin to suffer memory loss by their early 60s, but it can affect some people as young as their 40s, and there are no effective treatments.
By studying rare, inherited forms of brain diseases, the team of researchers led by Washington University School of Medicine in St. Louis believe they will learn a great deal about how to treat the more common forms of those disorders.
The researchers gathered skin samples from patients with frontotemporal dementia who were known to have a specific mutation in the MAPT gene, and then converted the patients' skin cells into induced pluripotent stem cells, which have the ability to grow and develop into any cell type in the body.
The study was published Thursday in the journal Translational Psychiatry.
They treated these stem cells with compounds that coaxed them to grow and develop into neurons, which also had the MAPT mutation. Then, using gene-editing technology called CRISPR, the researchers eliminated the mutation in some neurons but not others and observed what happened.
In neurons with the mutation, the researchers found alterations in 61 genes, including genes that make GABA receptors on brain neurons.
GABA receptors are the major inhibitory receptors in the brain, and they are key to several types of communication between brain cells.
The researchers identified similar disruptions in genes that make GABA receptors when they did experiments in animal models and analyzed brain tissue from patients who had died with frontotemporal dementia.
They also looked at findings from a genomewide association study of more than 2,000 patients with frontotemporal dementia and more than 4,000 without the disorder. That analysis also pointed to GABA-related genes as potential targets.
"Using our stem cell-derived neurons, we have the opportunity, in human tissue, to target some of those GABA genes in advance of the neurodegeneration we see in the postmortem tissue we study," said Oscar Harari, an assistant professor of psychiatry and a co-senior author of the study.
"Importantly, the approach we are using allows us to zero in on genes and pathways that are altered in cells and in patient brains that may be influenced by compounds already approved by the FDA," said Celeste M. Karch, an assistant professor of psychiatry and one of the study's senior authors.
