By Fen-Biao Gao | March twenty fourth, 2023
UMass Chan Medical Faculty Professor of Neurology at Fen-Biao Gao explores how frontotemporal dementia — the syndrome affecting Bruce Willis and which often impacts individuals beneath the age of 60 — modifications the mind and the way analysis is untangling FTD’s genetic causes.
Round 55 million individuals worldwide undergo from dementia resembling Alzheimer’s illness. Just lately, the actor Bruce Willis was recognized with frontotemporal dementia, or FTD, a uncommon kind of dementia that sometimes impacts individuals ages 45 to 64. In distinction to Alzheimer’s, during which the key preliminary symptom is reminiscence loss, FTD sometimes entails modifications in habits.
The preliminary signs of FTD could embody modifications in character, habits and language manufacturing. For example, some FTD sufferers exhibit inappropriate social habits, impulsivity and lack of empathy. Others battle to seek out phrases and to specific themselves. This insidious illness might be particularly arduous for households and family members to take care of. There isn’t a remedy for FTD, and there aren’t any efficient therapies.
As much as 40% of FTD instances have some household historical past, which suggests a genetic trigger could run within the household. Since researchers recognized the primary genetic mutations that trigger FTD in 1998, greater than a dozen genes have been linked to the illness. These discoveries present an entry level to find out the mechanisms that underlie the dysfunction of neurons and neural circuits within the mind and to make use of that information to discover potential approaches to therapy.
I’m a researcher who research the event of FTD and associated issues, together with the motor neuron illness amyotrophic lateral sclerosis, or ALS. ALS, also called Lou Gehrig’s illness, ends in progressive muscle weak point and dying. Uncovering the similarities in pathology and genetics between FTD and ALS might result in new methods to deal with each illnesses.
Genetic causes of FTD
Genes comprise the directions cells use to make the proteins that perform capabilities important to life. Mutated genes may end up in mutated proteins that lose their regular operate or change into poisonous.
How mutated proteins contribute to FTD has been beneath intense investigation for many years. For example, one of many key proteins in FTD, referred to as tau, helps stabilize sure constructions in neurons and might type clumps in diseased brains. One other key protein, progranulin, regulates cell progress and part of the cell referred to as the lysosome that breaks down mobile waste merchandise.
Remarkably, the most typical genetic mutation in FTD – in a gene referred to as C9orf72 – additionally causes ALS. Actually, aside from the mutations in genes that encode for tau and progranulin, most genetic mutations that trigger FTD additionally trigger ALS. One other protein, TDP-43, types clumps within the brains of over 95% of ALS instances and nearly half of FTD instances. Thus, these issues share shut hyperlinks in genetics and pathology.
Modifier genes
The identical genetic mutation could cause FTD in a single affected person, ALS in one other or signs of each FTD and ALS on the similar time. Remarkably, some individuals who carry these genetic mutations could haven’t any apparent signs for many years.
One motive the identical mutation could cause each FTD and ALS is that, along with way of life and environmental elements, different genes may additionally affect whether or not mutated genes result in illness. Figuring out these modifier genes in FTD, ALS and different neurodegenerative illnesses might result in new therapy approaches by boosting the exercise of people who defend in opposition to illness or suppressing the exercise of people who promote illness.
Modifier genes have lengthy been a spotlight of analysis in my laboratory on the College of Massachusetts Chan Medical Faculty. When my laboratory was nonetheless in San Francisco, we collaborated with neurologist Bruce Miller and generated the primary stem cell traces from FTD sufferers with mutations in progranulin and C9orf72. These stem cells might be was neurons for researchers to check in a petri dish. My group additionally makes use of fruit flies to determine modifier genes after which check how they affect illness in neurons from sufferers with FTD or ALS.
For example, in shut collaboration with cell biologist J. Paul Taylor, my laboratory was among the many first to find a small subset of modifier genes that assist transport molecules into or out of the nucleus of a neuron. We additionally found modifier genes that encode for some proteins that assist restore broken DNA. Concentrating on these modifier genes utilizing gene-silencing methods developed by Nobel laureate Craig Mello and different researchers at UMass Chan might supply potential therapies.
Treating behavioral modifications in FTD
As a result of the mind is an especially advanced organ, it may be very obscure what causes character and behavioral modifications in FTD sufferers.
Through the years, my group has used mice to check the causes of those modifications. For example, we discovered that the decreased social interplay we noticed in mice engineered to have FTD is linked to 2 completely different illness proteins in the identical a part of the mind, suggesting that this symptom could also be brought on by defects in the identical neural circuit. These deficits might be reversed by injecting a molecule referred to as microRNA-124 into the prefrontal cortex, the a part of the mind that controls social behaviors.
Furthermore, with my longtime collaborator neuroscientist Wei-Dong Yao, our labs discovered that mice with FTD have defects on the synapses on this a part of the mind. Synapses are areas the place neurons are in touch with one another and play an necessary function in transporting data within the nervous system. Just lately, he discovered that lack of empathy in one other mouse mannequin of FTD might be reversed by growing exercise within the prefrontal cortex.
Additional analysis to know the molecular mechanisms and mind circuitry behind FTD supply hope that its devastating signs, together with behavioral and character modifications, will probably be treatable sooner or later.
This text by UMass Chan Medical Faculty Professor of Neurology at Fen-Biao Gao is republished from The Dialog beneath a Inventive Commons license.
