Scientists at the MRC Molecular Biology Laboratory have identified TAF15 protein aggregates as a key factor in frontotemporal dementia, a discovery that could revolutionize diagnosis and treatment. This study also investigated the potential involvement of TAF15 in both frontotemporal dementia and motor neuron disease. Credit: SciTechDaily.com
Researchers have established the first potential therapeutic target for a type of early-onset dementia.
Most neurodegenerative diseases, including dementia, involve proteins that aggregate into filaments called amyloids. In most of these diseases, researchers have identified proteins that aggregate, making them available for diagnostic tests and treatments.
But in about 10% of frontotemporal dementia cases, scientists had not yet identified the rogue protein. Now, scientists have pinpointed the aggregate structure of the protein TAF15 in these cases.
Nature of frontotemporal dementia
Frontotemporal dementia is caused by degeneration of the frontal and temporal lobes of the brain, which control emotions, personality, behavior, and even speech and understanding of words.tend to start at a younger age Alzheimer’s disease The disease is most often diagnosed in people between the ages of 45 and 65, but can also affect younger and older people.
In a paper published today in a magazine NatureResearch led by scientists from . Medical Research Council (MRC) Molecular Biology LaboratoryResearchers from Cambridge, UK, and colleagues have identified aggregated protein structures that could serve as targets for the development of future diagnostic tests and treatments.
A breakthrough in molecular understanding
Dr. Benjamin Riskeldi-Falcon, who led the study at the MRC Molecular Biology Laboratory, said: “This discovery changes our understanding of the molecular basis of frontotemporal dementia. This is an unusual discovery regarding a new member of a small group of proteins known to aggregate in neurodegenerative diseases. be.
“Now that we have identified the key protein and its structure, we can begin to target it for the diagnosis and treatment of this type of frontotemporal dementia. Similar to strategies already in the pipeline that target Alzheimer’s disease.”
Discover new insights with advanced techniques
Researchers used state-of-the-art cryo-electron microscopy (cryo-EM) to study protein aggregates in the brains of four people with this type of frontotemporal dementia at atomic resolution. The donated brain was identified by Tamaryn Lashley of the Institute of Neurology at University College London’s Queen Square and Bernardino Getty of the Indiana University School of Medicine.
Scientists have long thought that a protein called FUS aggregates in this type of dementia, based on similarities with other neurodegenerative diseases.
Using cryo-EM, researchers at the MRC Molecular Biology Laboratory were able to determine that protein aggregates from each brain had the same atomic structure. Surprisingly, that protein was not FUS, but another protein called TAF15.
Dr Stefan Tetter from the MRC Molecular Biology Laboratory and lead author of the paper said: “This is an unexpected result because prior to this study, TAF15 was not known to form amyloid filaments in neurodegenerative diseases and did not form structures.” Ta. Cryo-EM is changing our understanding of the molecular pathology of dementia and neurodegenerative diseases more broadly by providing us with insights beyond the capabilities of previous technologies. ”
Dr. Ryskeldi-Falcon added: “Due to the technical challenges of performing cryo-EM, we were only able to observe the brains of four people. However, now that we know the key proteins and their structures, we are able to identify these abnormal protein aggregates in hundreds of patient samples. We may be able to develop tools to screen and test how widespread they are.”
Frontotemporal dementia and motor neuron disease
Some people with frontotemporal dementia also have motor neuron disease. Motor neuron disease is a condition in which muscle control is gradually lost. In this study, two of her brain donors showed signs of both diseases. In these people, the researchers identified the same aggregated TAF15 structures in brain regions associated with motor neuron disease.
“The presence of the same TAF15 aggregates in two patients with frontotemporal dementia and signs of motor neuron disease raises the possibility that TAF15 contributes to both diseases,” said Dr. Riskeldi-Falcon. It’s increasing,” he said. We are currently studying whether abnormally aggregated TAF15 is present in people with motor neuron disease despite the absence of frontotemporal dementia. ”
This study was funded by the Medical Research Council, Alzheimer’s Research UK and the USA. National Institutes of HealthAlzheimer’s Disease Society, Frontotemporal Degeneration Society, Swiss National Science Foundation, Leverhulme Trust.
Dr Charlotte Durkin, head of the Medical Research Council’s Molecular and Cellular Medicine Committee, said:
“Decades of world-leading research at the MRC Molecular Biology Laboratory has led to breakthrough advances in cryo-electron microscopy and won Dr. Richard Henderson the Nobel Prize in 2017. Frontal This latest study, identifying proteins associated with a type of temporal dementia, continues the success of the MRC LMB. Structures of dementia-related proteins by cryoEM, including the first structure of the key dementia protein tau In the elucidation of Knowing the identity and basic structure of these filaments in this rare form of early-onset dementia is essential for developing early diagnostic tests and drugs to combat filament formation. ”
Reference: “TAF15 amyloid filaments in frontotemporal lobar degeneration” Stephan Tetter, Diana Arseni, Alexey G. Murzin, Yazead Buhidma, Sew Y. Peak-Chew, Holly J. Garringer, Kathy L. Newell, Ruben Vidal, Liana G By Apostolova, Tamaryn Lashley, Bernardino Getty, Benjamin Riskeldi-Falcon, December 6, 2023. Nature.
DOI: 10.1038/s41586-023-06801-2