Most neurodegenerative diseases, including dementias, involve proteins aggregating into filaments called amyloids. For most of these diseases researchers have identified the proteins that aggregate, allowing them to target the proteins for diagnostic tests and treatments. However, for around 10 percent of cases of frontotemporal dementia (FTD), the most common form of dementia after Alzheimer’s disease, the rogue protein hasn’t been known.

Now, scientists headed by a team at have the Medical Research Council (MRC) Laboratory of Molecular Biology have pinpointed aggregated structures of the protein TAF15 in these cases. The findings could potentially offer up a new target for the future development of diagnostics and treatments.

Research lead Benjamin Ryskeldi-Falcon, PhD, 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 characterize Alzheimer’s disease.”

Inclusions of aggregated TAF15 (brown) in the brain of an individual with frontotemporal dementia. Scale bar, 50 μm.
Inclusions of aggregated TAF15 (brown) in the brain of an individual with frontotemporal dementia. Scale bar, 50 μm. [S. Tetter/MRC Laboratory of Molecular Biology.]
Ryskeldi-Falcon and colleagues reported on their findings in Nature, in a paper titled “TAF15 amyloid filaments in frontotemporal lobar degeneration,” in which they concluded, “The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.”

Frontotemporal dementia is caused by frontotemporal lobar degeneration (FTLD), which is degeneration of the brain’s frontal and temporal lobes that control emotions, personality and behavior, as well speech and understanding of words. FTD tends to start at a younger age than does Alzheimer’s disease, and may be diagnosed in people aged 45–65, although it can also affect younger or older people.

“The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins,” the authors wrote, and in the majority of FTD cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes. Scientists had long thought for the remaining cases a protein called FUS aggregated, based on similarities with other neurodegenerative diseases. “The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma),” the team continued.

Dr Benjamin Ryskeldi-Falcon.
Dr Benjamin Ryskeldi-Falcon. [MRC Laboratory of Molecular Biology]
For their reported study the researchers used cutting-edge cryo-electron microscopy (cryo-EM) to study at atomic resolution protein aggregates from the brains of four people who had this type of frontotemporal dementia. The donated brains were identified by Tammaryn Lashley, PhD,  at the University College London Queen Square Institute of Neurology, and Bernardino Ghetti, MD, at the Indiana University School of Medicine.

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. But surprisingly, they found that the protein involved was not FUS, it was another protein called TAF15. “Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself,” they noted. TAF, FUS, and another protein, Ewing’s sarcoma (EWS) are homologous RNA-binding proteins that are collectively known as the FET proteins, the investigators further explained. “Owing to FET protein immunoreactivity, FTLD–FUS has also been referred to as FTLD–FET, a more comprehensive term.”

First author Stephan Tetter, PhD, also from the MRC Laboratory of Molecular Biology, said their finding was unexpected. “ … before this study, TAF15 was not known to form amyloid filaments in neurodegenerative diseases and no structures of the protein existed.”

Identical structures of amyloid filament structures from four individuals with frontotemporal lobar degeneration. Filament cross-sections are shown. Resolutions are indicated in Å. Sale bars, 50 nm.
Identical structures of amyloid filament structures from four individuals with frontotemporal lobar degeneration. Filament cross-sections are shown. Resolutions are indicated in Å. Scale bars, 50 nm. [S. Tetter/MRC Laboratory of Molecular Biology]
Some people who have frontotemporal dementia also have motor neuron disease, a condition in which individuals progressively lose control over their muscles. 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. The results, the team wrote, “suggest that the formation of TAF15 amyloid filaments can be associated with motor neuron pathology and may underlie a disease spectrum of FTLD and motor neuron disease.”

Ryskeldi-Falcon added, “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.”

In their conclusion, the team stated, “The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease … Together these results suggest that the formation of TAF15 amyloid filaments characterizes FTLD–FET, thereby adding TAF15 to the small group of proteins that form amyloid filaments associated with neurodegenerative disease alongside proteins such as tau, TDP-43 and α-synuclein.”

Tetter commented, “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.” As Ryskeldi-Falcon further pointed out,  “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.”

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