Early-onset dementia linked to newly identified protein

Researchers discovered abnormal TAF15 protein clusters in the brains of people with early-onset dementia, a type known as frontotemporal dementia. Unlike most cases, where the aggregating proteins are identified, about 10% of frontotemporal dementia cases lacked a known culprit. 

Now, researchers have found aggregated TAF15 proteins in these cases. Frontotemporal dementia affects the brain’s frontal and temporal lobes, impacting emotions, personality, behavior, speech, and word understanding. Typically diagnosed between ages 45 and 65, it often occurs earlier than Alzheimer’s disease.

Scientists used advanced cryo-electron microscopy to study protein clusters in the brains of four people with frontotemporal dementia. Initially believed to involve the FUS protein, the study revealed, through cryo-EM, that the aggregates had the same atomic structure, but surprisingly, it wasn’t FUS. Instead, it was another protein called TAF15. 

The brains used for the study were donated by individuals identified by Tammaryn Lashley at the University College London Queen Square Institute of Neurology and Bernardino Ghetti at the Indiana University School of Medicine.

Dr Stephan Tetter, also from the MRC LMB, who is the first author on the paper, said, “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 beyond previous technologies’ capabilities.”

Dr. Ryskeldi-Falcon added, “The technical challenge of performing cryo-EM meant that we were only able to look at the brains of four individuals. However, now that we know the key protein and its structure, we have the potential to develop tools to screen for these abnormal protein aggregates in hundreds of patient samples to test how widespread they are.”

Some people with frontotemporal dementia also develop motor neuron disease, where muscle control is progressively lost. In a study, two brain donors showed signs of both conditions, and researchers identified the same TAF15 aggregates in areas linked to motor neuron disease. Dr. Ryskeldi-Falcon noted this shared pattern, suggesting TAF15 might play a role in both disorders. The study, funded by organizations like MRC and Alzheimer’s Research UK, aims to explore if abnormal TAF15 aggregation exists in those with motor neuron disease without frontotemporal dementia.

The MRC Laboratory of Molecular Biology, known for its pioneering work in cryoelectron microscopy, has successfully revealed protein structures linked to frontotemporal dementia. This builds on their prior achievements, including the Nobel Prize-winning work of Dr. Richard Henderson in 2017. 

The study, leveraging cryoEM, identifies the protein associated with early-onset dementia, aiding the understanding of dementia-related protein structures. This knowledge is crucial for developing early diagnostic tests and drugs to counteract their formation, showcasing the MRC LMB’s ongoing contributions to dementia research.

Journal reference:

1. Tetter, S., Arseni, D., Murzin, A.G. et al. TAF15 amyloid filaments in frontotemporal lobar degeneration. Nature. DOI: 10.1038/s41586-023-06801-2.