UMass Chan Medical College’s Frontotemopral Dementia Analysis Heart founding director Fen-Biao Gao explains how FTD — the syndrome affecting Wendy Williams — modifications the mind.
Round 55 million individuals worldwide undergo from dementia comparable to Alzheimer’s illness. On Feb. 22, 2024, it was revealed that former discuss present host Wendy Williams had been identified with frontotemporal dementia, or FTD, a uncommon sort of dementia that usually impacts individuals ages 45 to 64. Bruce Willis is one other celeb who was identified with the syndrome, in keeping with his household. In distinction to Alzheimer’s, through which the foremost preliminary symptom is reminiscence loss, FTD usually includes modifications in habits.
The preliminary signs of FTD could embrace modifications in persona, habits and language manufacturing. As an illustration, some FTD sufferers exhibit inappropriate social habits, impulsivity and lack of empathy. Others wrestle to search out phrases and to specific themselves. This insidious illness might be particularly exhausting for households and family members to cope with. There isn’t any treatment 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 remedy.
I’m a researcher who research the event of FTD and associated problems, together with the motor neuron illness amyotrophic lateral sclerosis, or ALS. ALS, also referred to as Lou Gehrig’s illness, leads to progressive muscle weak point and loss of life. Uncovering the similarities in pathology and genetics between FTD and ALS might result in new methods to deal with each ailments.
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 perform or turn into poisonous.
How mutated proteins contribute to FTD has been underneath intense investigation for many years. As an illustration, one of many key proteins in FTD, referred to as tau, helps stabilize sure constructions in neurons and may type clumps in diseased brains. One other key protein, progranulin, regulates cell development and part of the cell referred to as the lysosome that breaks down mobile waste merchandise.
Remarkably, the commonest genetic mutation in FTD – in a gene referred to as C9orf72 – additionally causes ALS. In actual fact, other than the mutations in genes that encode for tau and progranulin, most genetic mutations that trigger FTD additionally trigger ALS. One other protein, TDP-43, kinds clumps within the brains of over 95% of ALS instances and virtually half of FTD instances. Thus, these problems share shut hyperlinks in genetics and pathology.
Modifier genes in FTD
The identical genetic mutation may 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 cause the identical mutation may cause each FTD and ALS is that, along with way of life and environmental components, different genes can also affect whether or not mutated genes result in illness. Figuring out these modifier genes in FTD, ALS and different neurodegenerative ailments might result in new remedy approaches by boosting the exercise of people who shield 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 College. 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 became neurons for researchers to review in a petri dish. My staff additionally makes use of fruit flies to establish modifier genes after which check how they affect illness in neurons from sufferers with FTD or ALS.
As an illustration, 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 provide potential therapies.
Treating behavioral modifications in FTD
As a result of the mind is an especially complicated organ, it may be very obscure what causes persona and behavioral modifications in FTD sufferers.
Through the years, my staff has used mice to review the causes of those modifications. As an illustration, we discovered that the diminished social interplay we noticed in mice engineered to have FTD is linked to 2 totally different illness proteins in the identical a part of the mind, suggesting that this symptom could also be attributable to defects in the identical neural circuit. These deficits could possibly 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 info within the nervous system. Just lately, he discovered that lack of empathy in one other mouse mannequin of FTD could possibly be reversed by rising exercise within the prefrontal cortex.
Additional analysis to know the molecular mechanisms and mind circuitry behind FTD provide hope that its devastating signs, together with behavioral and persona modifications, shall be treatable sooner or later.
