Protein connected to early-onset dementia paves the way to innovative new treatments
[Dec. 8, 2023: JD Shavit, The Brighter Side of News]
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Neurodegenerative diseases, including various forms of dementia, have long been a subject of intensive research and medical scrutiny. Many of these devastating conditions involve the aggregation of proteins into abnormal filaments known as amyloids. While researchers have successfully identified the proteins responsible for these aggregates in most cases, approximately 10% of frontotemporal dementia cases had remained elusive, until now.
A groundbreaking study, led by scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, UK, has unveiled a new player in the realm of neurodegenerative diseases – the protein TAF15.
Frontotemporal dementia, distinct from Alzheimer's disease, affects the frontal and temporal lobes of the brain, impacting emotions, personality, behavior, as well as speech and language abilities. Unlike Alzheimer's, this condition often strikes at a younger age, typically afflicting individuals between 45 and 65, although it can also affect those both younger and older.
Benjamin Ryskeldi-Falcon. (CREDIT: UCL)
In a recent publication in the prestigious journal Nature, researchers have revealed their groundbreaking findings, which promise to reshape our understanding of this debilitating disease and potentially pave the way for innovative diagnostic tools and treatments.
Identifying TAF15: A Transformative Discovery
Dr. Benjamin Ryskeldi-Falcon, who spearheaded the research at the MRC Laboratory of Molecular Biology, expressed the profound implications of their findings, stating, "This discovery transforms our understanding of the molecular basis of frontotemporal dementia. It is a rare finding of a new member of the small group of proteins known to aggregate in neurodegenerative disease."
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The study utilized cutting-edge cryo-electron microscopy (cryo-EM) techniques to scrutinize protein aggregates in the brains of four individuals afflicted with this form of frontotemporal dementia. These donated brains were identified by experts Tammaryn Lashley at the University College London Queen Square Institute of Neurology and Bernardino Ghetti at the Indiana University School of Medicine.
Prior to this groundbreaking research, scientists had believed that a protein called FUS was responsible for the abnormal aggregation seen in this type of dementia, based on similarities with other neurodegenerative diseases. However, employing the power of cryo-EM, the researchers at the MRC Laboratory of Molecular Biology made an unexpected revelation: the culprit was not FUS but rather a previously unassociated protein, TAF15.
Dr. Stephan Tetter, another key figure in the study, noted the significance of this surprising discovery, saying, "This is an unexpected result because, before this study, TAF15 was not known to form amyloid filaments in neurodegenerative diseases and no structures of the protein existed. Cryo-EM is transforming our understanding of the molecular pathology of dementia and neurodegenerative diseases more broadly by giving us insights that were beyond the capabilities of previous technologies."
Cryo-EM structure of TAF15 amyloid filaments from FTLD–FET. Domain organization of TAF15. The region comprising the ordered core of TAF15 amyloid filaments is indicated. RRM, RNA recognition motif; ZnF, zinc finger domain. (CREDIT: Nature)
With the identification of TAF15 and its atomic structure, the door has been opened to potentially revolutionary advancements in the diagnosis and treatment of frontotemporal dementia. Dr. Ryskeldi-Falcon stated, "Now that we have identified the key protein and its structure, we can start to target it for the diagnosis and therapy of this type of frontotemporal dementia, similar to strategies already in the pipeline for targeting the aggregates of amyloid-beta and tau proteins that characterize Alzheimer's disease."
Although the study's scope was limited to examining the brains of just four individuals, the technical achievement of identifying TAF15 and its structure holds immense promise. It lays the foundation for the development of tools capable of screening for these abnormal protein aggregates in a larger patient cohort, potentially shedding light on the prevalence of this previously unidentified protein's involvement in frontotemporal dementia.
Cryo-EM characterization of amyloid filaments from individuals with FTLD–FET. Representative cryo-EM micrograph of the sarkosyl-insoluble fraction of frontotemporal cortex grey matter from individual 1 with FTLD–FET. Abundant amyloid filaments are indicated by arrows. (CREDIT: Nature)
Frontotemporal dementia does not always manifest in isolation. Some individuals with this condition also exhibit symptoms of motor neuron disease, a debilitating condition characterized by the progressive loss of muscle control. In the study, two of the brain donors had both frontotemporal dementia and motor neuron disease. Remarkably, the researchers detected the same aggregated structure of TAF15 in brain regions associated with motor neuron disease.
This intriguing finding raises the possibility that TAF15 may play a role in both diseases, suggesting a potential link between frontotemporal dementia and motor neuron disease. Dr. Ryskeldi-Falcon affirmed their commitment to further exploration, stating, "The presence of the same TAF15 aggregates in two individuals who had frontotemporal dementia and signs of motor neuron disease raises the possibility that TAF15 may contribute to both diseases. We are now studying whether aberrant aggregated TAF15 is present in people who have motor neuron disease in the absence of frontotemporal dementia."
This groundbreaking research received support from various organizations and institutions dedicated to advancing the understanding and treatment of neurodegenerative diseases. The study was funded by the Medical Research Council, Alzheimer's Research UK, the US National Institutes of Health, the Alzheimer's Society, the Association for Frontotemporal Degeneration, the Swiss National Science Foundation, and the Leverhulme Trust.
Dr. Charlotte Durkin, Head of the Medical Research Council's Molecular and Cellular Medicine Board, praised the significance of this research, saying, "Knowing the identity and basic structure of these filaments in this rare form of early-onset dementia is vital to developing early diagnostic tests and drugs to combat their formation." The study's success underscores the importance of continued scientific exploration in the quest to unlock the mysteries of neurodegenerative diseases and offer hope to those affected by them.
As scientists continue to explore the links between TAF15, frontotemporal dementia, and motor neuron disease, the hope is that this discovery will pave the way for the development of effective therapeutic strategies and ultimately improve the lives of individuals affected by these devastating conditions. With continued research and innovation, the future holds promise for a deeper understanding of neurodegenerative diseases and, ultimately, the development of targeted treatments that could offer relief to countless individuals and their families.
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