Scientists have identified abnormal aggregates of a protein called TAF15 in the brains of individuals with early-onset dementia, known as frontotemporal dementia, where the cause was not previously known.
The research led by scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology, in Cambridge, UK, could provide a target for the future development of diagnostic tests and treatments.
Dr Benjamin Ryskeldi-Falcon, who led the study, said: “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.
“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 characterise Alzheimer’s disease.”
The scientists used cryo-electron microscopy (cryo-EM) to study protein aggregates from the brains of four people who had this type of frontotemporal dementia at atomic resolution.
In this type of dementia, scientists had long thought that a protein called FUS aggregated, based on similarities with other neurodegenerative diseases.
Using cryo-EM, the researchers at the MRC Laboratory of Molecular Biology were able to identify that the protein aggregates from each brain had the same atomic structure. Surprisingly, the protein was not FUS – it was another protein called TAF15.
Dr Stephan Tetter, also from the MRC Laboratory of Molecular Biology, who is 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 that were beyond the capabilities of previous technologies.”
Motor neuron disease
Some people who have frontotemporal dementia also have motor neuron disease (MND). In this study, two of the individuals who donated their brains had signs of both diseases. For these individuals, the researchers identified the same aggregated structure of TAF15 in brain regions associated with motor neuron disease.
Dr Ryskeldi-Falcon said: “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 neurone disease in the absence of frontotemporal dementia.”
A new whitepaper providing guidance for the MND drug discovery community was recently published to ensure that future drug discovery and development efforts have the best chance of successfully translating from the lab to the clinic.