Potential Target Found for Treating Frontotemporal Dementia
Frontotemporal dementia—triggered by cell death in the front and sides of the brain—accounts for about one-fourth of all cases of early-onset dementia. It typically strikes individuals between the ages of 40 and 64 and can bring about significant changes in a person’s personality and behavior, including the loss of the ability to communicate.
Now, scientists at the University of California, Los Angeles (UCLA) have discovered that a certain signaling pathway plays a key role in the brain disorder and may offer a potential target for treatment.
“A family history exists for nearly half of the frontotemporal dementia patients we see, suggesting a genetic component for the disease,” said Dr. Daniel Geschwind, a professor of neurology at the David Geffen School of Medicine at UCLA and professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA.
“Our goal was to reveal what happens on a molecular level that causes the neuron death leading to this devastating disease,” said Geschwind, who also holds the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics.
Previous studies have linked frontotemporal dementia with a mutation in the gene for granulin, a protein which regulates cell growth and survival. Research revealed that the gene mutation reduces the levels of granulin by half.
“Until now, little has been known about granulin’s function in the brain,” Geschwind said. “We wanted to explore whether a granulin shortage kickstarts the cell death that precedes dementia. We also were searching for naturally occurring protective responses that we could target to help alleviate the disease’s symptoms.”
Geschwind and his team studied granulin’s role on three fronts: in cell culture, in a gene-knockout mouse model and in brain tissue from deceased individuals with dementia.
“Cell death is easy to observe in brain tissue removed from patients after their death,” Geschwind said. “We pursued two other approaches to determine the mechanism behind brain-cell survival and uncover how early it occurs in the disease.”
The researchers worked on a genetic analysis of granulin-deficient neurons made from human brain stem cells. They used a powerful method that allowed them to see the entire genome and search for networks of highly correlated genes.
“We discovered that a drop in granulin sabotaged brain cells’ survival and boosted activity of Wnt, a major signaling pathway,” Geschwind said. “Within this pathway, we identified a major increase in a specific receptor that Wnt binds to on the cell surface. This change occurred early in the disease process in both living mice and culture.”
The scientists discovered that Wnt signaling through the receptor FZD2 was stronger in mice that were granulin-deficient. Reducing the receptor resulted in more cell death, while increasing it encouraged neuron survival, suggesting that Wnt signaling is probably a defensive response to the disorder.
“We believe that Wnt boosts FZD2 to help protect brain-cell survival during the early stages of dementia,” Geschwind said. “Our findings suggest that increasing this receptor and other parts of the Wnt pathway may provide a new drug target to treat this disease.”
The findings are published in the journal Neuron.
Source: University of California
Pedersen, T. (2018). Potential Target Found for Treating Frontotemporal Dementia. Psych Central. Retrieved on May 30, 2020, from https://psychcentral.com/news/2011/09/25/potential-target-found-for-treating-frontotemporal-dementia/29751.html