MAPT Gene Variant Implicated In Frontotemporal Dementia

A lone gene mutation that causes an inherited form of frontotemporal dementia makes it harder for neurons in the brain to communicate with one another, leading to neurodegeneration, an international team of researchers, led by Washington University School of Medicine in St. Louis, has found.

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.

The new findings zero in on the microtubule-associated protein tau (MAPT) gene. That gene expresses a protein called tau, which also has been associated with cognitive decline in Alzheimer’s disease.

Improving Disrupted Pathways

Identifying the downstream effects of the MAPT mutation could help identify new treatment targets for frontotemporal dementia, Alzheimer’s disease and other tau-related illnesses, including Parkinson’s disease.

“We have demonstrated that we can capture changes in human cells cultured in a dish that also are appearing in the brains of individuals suffering with frontotemporal dementia. 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. We want to evaluate whether any of these compounds could prevent memory loss, or even restore memory, in people with frontotemporal dementia by improving the function of these pathways that have been disrupted,”

said Celeste M. Karch, Ph.D., an assistant professor of psychiatry and one of the study’s senior authors.

Potential Therapeutic Target

Karch, with co-senior author Carlos Cruchaga, Ph.D., an associate professor of psychiatry, and the other co-senior author, Oscar Harari, Ph.D., an assistant professor of psychiatry, gathered skin samples from patients with frontotemporal dementia who were known to have a specific mutation in the MAPT gene.

The researchers 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 researchers treated these stem cells with compounds that coaxed them to grow and develop into neurons, which also had the MAPT mutation.

differential expression in human brains from MAPT p.R406W carriers compared with normal controls
328 genes were tested for differential expression in human brains from MAPT p.R406W carriers compared with normal controls.
Credit: Jiang S, et al. CC-BY

Then, using gene-editing technology called CRISPR, the researchers eliminated the mutation in some neurons but not others and observed what happened.

“We found differences in genes and pathways related to cellular communication, suggesting the mutation alters neurons’ ability to communicate. The initial mutation in MAPT is the key change that starts the disease, and it is a potential target for therapy, but there are other genes downstream from the MAPT gene that also are good targets that may be used to treat the disease,”

said Cruchaga.

GABA Receptors

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.

Human iPSC-derived cortical neurons from MAPT p.R406W carriers and isogenic controls served as a discovery cohort to identify genes affected by the MAPT p.R406W mutation
Human iPSC-derived cortical neurons from MAPT p.R406W carriers and isogenic controls served as a discovery cohort to identify genes affected by the MAPT p.R406W mutation.
Credit: Jiang S, et al. CC-BY

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 Harari. “So, at least in cell cultures, we can learn whether potential therapies prevent the damage caused by inherited forms of frontotemporal dementia.”

And by studying rare, inherited forms of brain diseases, the researchers believe they will learn a great deal about how to treat the more common forms of those disorders.

“Genetic forms of frontotemporal dementia and Alzheimer’s disease are caused by rare mutations. But they have much in common with the more typical cases of those diseases. If we understand these cases caused by inherited mutations, we also should better understand the common forms of these diseases,”

Cruchaga said.

The research was supported by grants from the National Institutes of Health, the Tau Consortium, and the Alzheimer Association.

Shan Jiang, Natalie Wen, Zeran Li, Umber Dube, Jorge Del Aguila, John Budde, Rita Martinez, Simon Hsu, Maria V. Fernandez, Nigel J. Cairns, Dominantly Inherited Alzheimer Network (DIAN), International FTD-Genomics Consortium (IFGC), Oscar Harari, Carlos Cruchaga & Celeste M. Karch
Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP
Translational Psychiatry volume 8, Article number: 265 (2018)

Top Image: Sidhartha Mahali


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