In a study published in the scientific journal Nature, researchers in the United Kingdom discovered that a previously known protein may play a role in the development of an FTD subtype once thought to be associated with the FUS protein.

The abnormal accumulation of the proteins TDP-43 and tau have been previously identified as playing a significant role in the development of FTD, being associated with 50% and 40% of FTD cases, respectively. FUS accumulations were thought to occur in the remaining 10% of cases. However, FUS mutations have not yet been observed in FTLD and FUS has not yet been detected in accumulations that occur in brain tissue from an FTLD patient.

Benjamin Ryskeldi-Falcon, PhD, BSc, and his team at the Medical Research Council’s Laboratory of Molecular Biology discovered that, while the protein in play was related to FUS, it was a different protein altogether. The protein, called “TATA-binding protein-associated factor 15,” or TAF15, plays a role in regulating what is known as gene expression, the process where information stored in a gene is used to produce RNAs that in turn are the barcode for creating a protein . TAF15 and FUS play similar roles and are structurally similar, being in a family known as “FET proteins.”

“It is a rare finding of a new member of the small group of proteins known to aggregate in neurodegenerative disease,” Dr. Ryskeldi-Falcon told Neuro Rehab Times. “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.”

The team analyzed samples from four people diagnosed with FTD with a cutting-edge technology called “cryo-electron microscopy” (cryo-EM) that allowed them to look for amyloids at the atomic level. Using cryo-EM, Dr. Ryskeldi-Falcon and his team could identify TAF15 by the sequence of amino acids the protein is made of. While the researchers found plenty of TAF15 amyloids, they found none made of FUS proteins.

“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,” said Stephan Tetter, PhD, the first author of the study. “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.”

While the complexity of cryo-EM technology meant that the team could only review samples from four people, Dr. Ryskeldi-Falcon says now that TAF15’s role and its structure have been discovered, tools can be developed to screen for aggregations of the protein more easily. Additionally, Dr. Ryskeldi-Falcon highlighted that two of the people who contributed samples for the study had motor neuron disease.

“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,” Dr. Ryskeldi-Falcon said. “We are now studying whether aberrant aggregated TAF15 is present in people who have motor neuron disease in the absence of frontotemporal dementia.”

The discovery of a novel protein associated with FTD opens the door to new avenues for the study of disease mechanisms. Additionally, identifying TAF15 opens the door to new diagnostic and therapeutic approaches for FTD caused by FET proteins.

Study co-author Tammaryn Lashley, MD, PhD, is a two-time recipient of funding from the AFTD Biomarkers Initiative, receiving grants in 2022 and 2018. Another co-author, Bernardino Ghetti, MD, is a member of the AFTD Medical Advisory Council.

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