Worldwide, approximately 55 million people suffer from dementia, such as Alzheimer’s disease. On February 22, 2024, it was revealed that former talk show host Wendy Williams had been diagnosed with frontotemporal dementia or FTD, a rare form of dementia that typically affects people aged 45 to 64. Bruce Willis is another celebrity who has been diagnosed with the syndrome, according to his family. Unlike Alzheimer’s disease, where the main initial symptom is memory loss, FTD is usually accompanied by behavioral changes.
The first symptoms of FTD may include changes in personality, behavior, and language production. For example, some FTD patients exhibit inappropriate social behavior, impulsivity, and loss of empathy. Others struggle to find words and express themselves. This insidious disease can be especially difficult for families and loved ones to cope with. There is no cure for FTD and there are no effective treatments.
Up to 40% of FTD cases have a family history, meaning a genetic cause may run in the family. Since researchers identified the first genetic mutations that cause FTD in 1998, more than a dozen genes have been linked to the disease. These discoveries provide a starting point to determine the mechanisms underlying the dysfunction of neurons and neural circuits in the brain and to use that knowledge to investigate potential treatment approaches.
I am a researcher studying the development of FTD and related conditions, including the motor neuron disease amyotrophic lateral sclerosis, or ALS. ALS, also known as Lou Gehrig’s disease, results in progressive muscle weakness and death. Uncovering the similarities in pathology and genetics between FTD and ALS could lead to new ways to treat both diseases.
Genetic causes of FTD
Genes contain the instructions that cells use to make the proteins that perform functions essential to life. Mutated genes can result in mutated proteins that lose their normal function or become toxic.
How mutated proteins contribute to FTD has been intensively investigated for decades. For example, one of the key proteins in FTD, called tau, helps stabilize certain structures in neurons and can form clumps in diseased brains. Another important protein, progranulin, regulates cell growth and a part of the cell called the lysosome, which breaks down cellular waste products.
Remarkably, the most common genetic mutation in FTD – in a gene called C9orf72 – also causes ALS. In fact, most of the genetic mutations that cause FTD, in addition to the mutations in genes encoding tau and progranulin, also cause ALS. Another protein, TDP-43, forms clumps in the brains of more than 95% of ALS cases and nearly half of FTD cases. These conditions therefore have close links in terms of genetics and pathology.
Modifying genes
The same genetic mutation can cause FTD in one patient, ALS in another, or cause symptoms of both FTD and ALS at the same time. Remarkably, some people who carry these genetic mutations have no obvious symptoms for decades.
One reason why the same mutation can cause both FTD and ALS is that in addition to lifestyle and environmental factors, other genes can influence whether mutated genes lead to disease. Identifying these modifying genes in FTD, ALS and other neurodegenerative diseases could lead to new treatment approaches by boosting the activity of those that protect against disease or suppressing the activity of those that promote disease.
Modifier genes have long been a focus of research in my laboratory at the University of Massachusetts Chan Medical School. When my lab was still in San Francisco, we worked with neurologist Bruce Miller and generated the first stem cell lines from FTD patients with mutations in progranulin and C9orf72. These stem cells can be converted into neurons that researchers can study in a petri dish. My team is also using fruit flies to identify modifying genes and then test how they affect the disease in neurons from patients with FTD or ALS.
For example, working closely with cell biologist J. Paul Taylor, my lab was among the first to discover a small subset of modifier genes that help transport molecules into or out of a neuron’s nucleus. We also discovered modification genes that code for some proteins that help repair damaged DNA. Targeting these modifying genes using gene silencing techniques developed by Nobel laureate Craig Mello and other researchers at UMass Chan could provide potential treatments.
Treatment of behavioral changes in FTD
Because the brain is an extremely complex organ, it can be very difficult to understand what causes personality and behavioral changes in FTD patients.
Over the years, my team has used mice to study the causes of these changes. For example, we found that the reduced social interaction we observed in mice engineered to have FTD is linked to two different disease proteins in the same part of the brain, suggesting that this symptom may be caused by defects in the same neural circuit. These deficits can be reversed by injecting a molecule called microRNA-124 into the prefrontal cortex, the part of the brain that controls social behavior.
In addition, our laboratories, together with the neuroscientist Wei-Dong Yao, who I have worked with for many years, have discovered that mice with FTD have defects in the synapses in this part of the brain. Synapses are areas where neurons contact each other and play an important role in transporting information in the nervous system. He recently discovered that the lack of empathy in another mouse model of FTD can be reversed by increasing activity in the prefrontal cortex.
Further research to understand the molecular mechanisms and brain circuits behind FTD offers hope that its devastating symptoms, including behavioral and personality changes, will be treatable in the future.
This is an updated version of an article originally published on February 22, 2023.
This article is republished from The Conversation, an independent nonprofit organization providing facts and trusted analysis to help you understand our complex world. It was written by: Fen-Biao Gao, UMass Chan Medical School
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Fen-Biao Gao receives and has previously received funding from the NIH, The Muscular Dystrophy Association, The Association for FTD, Target ALS Foundation, The ALS Association, The Tau Consortium, The Consortium for Frontotemporal Dementia Research, The Ricico Fund, The Cellucci Fund , Merck and Stealth BioTherapeutics. He works for the NIH as a member of the CMND Study Section, for The Muscular Dystrophy Association as a member of the Research Advisory Council, and for The Association for FTD as a member of the Scientific Review Panel.