TAKE AWAYS
- Scientists at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, UK, have identified a novel protein called TAF15 forming aggregated structures in cases of frontotemporal dementia, challenging previous assumptions about the condition;
- This discovery is a novel addition to the limited set of proteins recognized for aggregating in neurodegenerative disorders like Alzheimer’s; and
- This finding not only paves the way for advanced diagnostic tools and treatments; however, also raises the intriguing possibility that TAF15 may be linked to both frontotemporal dementia and motor neuron disease, shedding new light on these debilitating disorders.
Most neurodegenerative disorders, such as dementia, involve proteins clustering into filaments known as amyloids. In most cases, scientists have pinpointed the proteins responsible for this aggregation, enabling them to focus on these proteins for diagnostic assessments and therapies. However, in approximately 10% of frontotemporal dementia cases, researchers had not yet determined the specific protein responsible. Now, researchers have successfully identified the aggregated structures of the TAF15 protein in these particular cases. The findings were published in Nature.
Novel protein may contribute to frontotemporal dementia
Frontotemporal dementia arises from the deterioration of the brain’s frontal and temporal lobes, which oversee emotions, personality, behavior, language comprehension and speech. This condition typically manifests at an earlier age compared to Alzheimer’s disease, frequently being diagnosed in individuals between 45 and 65 years old. However, it can also present in individuals both younger and older.
In their new research, a team of scientists uncovered aggregated protein structures that may serve as a focal point for potential advancements in diagnostic assessments and therapies. With the identification of the key protein and its structure, the researchers are now poised to focus on it to diagnose and treat this specific form of frontotemporal dementia. This approach mirrors the strategies already in progress for targeting amyloid-beta and tau protein aggregates — hallmark features of Alzheimer’s disease.
Utilizing advanced cryo-electron microscopy to examine the brain
The scientists utilized advanced cryo-electron microscopy (cryo-EM) techniques to examine protein aggregates at an atomic level resolution in the brains of four individuals with this form of frontotemporal dementia. Until now, scientists had assumed that a protein named FUS was responsible for aggregation in this type of dementia, drawing parallels with other neurodegenerative disorders.
Utilizing cryo-electron microscopy (cryo-EM), the MRC Laboratory of Molecular Biology scientists successfully determined that the protein aggregates found in each brain shared an identical atomic structure. Surprisingly, the responsible protein was not FUS but another protein called TAF15. The researchers clarified that this outcome was unexpected, as prior to this study, TAF15 had not been recognized for its role in forming amyloid filaments in neurodegenerative conditions, and no information about its structural characteristics existed.
Cryo-EM is revolutionizing our comprehension of the molecular mechanisms underlying dementia and neurodegenerative diseases in a broader context by providing insights that were previously unattainable with earlier technologies. The researchers acknowledged that the intricate nature of conducting cryo-electron microscopy limited their examination to only four (4) individuals’ brains. Nevertheless, with our newfound knowledge of the pivotal protein and its structure, there is the prospect of creating tools for screening hundreds of patient samples to assess the extent of these abnormal protein aggregates.
Frontotemporal dementia and motor neuron disease
Some individuals affected by frontotemporal dementia also experience motor neuron disease, a condition characterized by a progressive loss of muscle control. In this investigation, two (2) individuals who had both conditions donated their brains for study. In these cases, the researchers detected the same aggregated form of the TAF15 protein in brain regions associated with motor neuron disease. The presence of identical TAF15 aggregates in two individuals who had both frontotemporal dementia and signs of motor neuron disease raises the possibility that TAF15 may contribute to the development of both disorders.
Further research needed to investigate the impact of TAF15
The research team is currently examining whether these abnormal TAF15 aggregates are present in individuals with motor neuron disease who do not exhibit symptoms of frontotemporal dementia. James Giordano, PhD, MPhil, Pellegrino Center Professor of Neurology and Biochemistry at Georgetown University Medical Center, not involved in this research, told Medical News Today that “this study further examined the possibility that additional abnormal proteins may be contributory to the neuropathological process of fronto temporal lobar degeneration and dementia (FTLD).”
“The study was well conducted and utilized a fairly broad sample of brain tissue taken from affected patients to evaluate the presence and extent of TAF protein, a variant abnormal protein constituent, which, together with other known abnormal proteins (such as characteristic tau and alpha-synuclein entities), are found in and contributory to the neurodegenerative processes of FTLD.”
— Dr. James Giordano
Dr. Giordano noted that “this study importantly, demonstrated that TAF protein is also present, albeit in somewhat lesser concentration, in the total proteinopathic constituency of the brains of these patients.” He noted that the study findings “further support and advance aspects of the amyloid hypothesis of neurodegenerative dementia. Further, the identification of TAF variant may serve as an important diagnostic marker, as well as a potential therapeutic target in the treatment of FTLD,” he explained.
Jennifer Bramen, Ph.D., Senior Research Scientist at the Pacific Neuroscience Institute in Santa Monica, CA, also not involved in this research, “frontotemporal lobe dementia (FTD) is an emotionally challenging disease with no cure.” Dr. Bramen concluded that “FTD is a heterogenous disease, making it more challenging to research. A better understanding of different subtypes could ultimately lead to more treatment options for patients.”
REFERENCE: Medical News Today (UK); 12 DEC 2023; Paul Ian Cross, PhD