Scientists have discovered a peculiar cluster of a specific protein in the brains of people with dementia praecox, pointing researchers to a potential cause, a diagnostic tool and ultimately a therapeutic target. Scientists at the Medical Research Council's (MRC) Molecular Biology Laboratory have discovered that the TAF15 protein accumulates abnormally during the development of frontotemporal dementia.
While extensive research is ongoing into protein aggregation and amyloid formation in other neurodegenerative diseases, the mechanisms of action in frontotemporal dementia have eluded science until now.
"This discovery changes our understanding of the molecular basis of frontotemporal dementia," said Dr. Benjamin Ryskeldi-Falcon, lead author of the study. "This is a rare discovery and is a new member of a small group of proteins known to aggregate in neurodegenerative diseases."
"Now that we have identified this key protein and its structure, we can begin to target it for diagnosis and treatment of this frontotemporal dementia, similar to strategies that target aggregation of the proteins amyloid-beta and tau that are characteristic of Alzheimer's disease," he added.
Researchers used atomic-resolution cryo-electron microscopy (cryo-EM) to study the brains of four deceased patients with frontotemporal dementia. They hope to learn more about the aggregation of the FUS protein, which has previously been thought to be a cause of disease. However, they discovered a new molecular villain in TAF15.
First author Stephan Tetter said: "This was an unexpected result because before this study, TAF15 was not known to form amyloid filaments in neurodegenerative diseases, nor did the structure of this protein exist. Cryo-electron microscopy has transformed our understanding of the molecular pathology of dementia and wider neurodegenerative diseases, providing us with insights that previous techniques could not provide."
What's more, the researchers discovered that TAF15 is also associated with motor neuron disease (MND), opening up new avenues of research in hopes of developing better diagnostics and treatments for this progressive neurological disorder.
"Some people with frontotemporal dementia also have motor neuron disease, a disease in which patients gradually lose control of their muscles," said Dr. Ryskeldi-Falcon. "In this study, two people who donated their brains had both conditions. In these people, the researchers found the same clustering of TAF15 in areas of the brain associated with motor neuron disease."
Frontotemporal dementia is a progressive degeneration of the brain's frontal and temporal lobes - the areas that regulate personality, behavior and emotion - and is called dementia praecox because it is most commonly diagnosed in people aged 45-65. In about 10 percent of cases, this "rogue" protein appears to be at the root.
It is still unclear how TAF15 contributes to dementia and MND, and what potential links there may be between them, but this is the next step for MRC scientists.
"We are now investigating whether abnormal aggregates of TAF15 are present in people with motor neuron disease in the absence of frontotemporal dementia," said Dr Ryskeldi-Falcon. He added: "The technical challenges of conducting cryo-electron microscopy meant we could only look at the brains of four people. However, now that we know the key proteins and their structures, it is possible to develop tools to screen for these abnormal protein aggregates in hundreds of patient samples to test how widespread they are."
The research was published in the journal Nature.