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HomeHealth & FitnessUnexpected protein linked to early-onset dementia in big discovery

Unexpected protein linked to early-onset dementia in big discovery

Unexpected protein linked to early-onset dementia in big discovery

Scientists have identified which protein forms the characteristic clusters of a type of early-onset dementia for which until now no firm suspect was known.

This discovery reportedly transforms understanding of the molecular basis of frontotemporal dementia (FTD), the second most common form of dementia after Alzheimer’s, whose symptoms typically appear earlier: between a person’s 40s and 50s.

People diagnosed with FTD experience changes in behavior, personality, language, and movement caused by the slow degeneration of the frontal and temporal lobes of the brain. Memory problems may appear later as the disease spreads to other regions of the brain.

But without knowing the true composition of the tangled protein deposits seen in some of the rarest cases of FTD, researchers had few targets to explore for potential therapies.

“This is a rare finding of a new member of the small group of proteins known to aggregate in neurodegenerative diseases,” said Benjamin Ryskeldi-Falcon, a molecular biologist at the MRC’s Laboratory of Molecular Biology (LMB) in the United Kingdom. who directed the study. study.

Binding proteins are what unites neurodegenerative diseases and what sets them apart.

Just as beta-amyloid and tau proteins are entangled in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, the SOD1 protein in amyotrophic lateral sclerosis (ALS), and Huntington’s, the eponymous protein that gives its name to Huntington’s disease, form sticky balls of different shapes in sick people. brain tissue.

Different subtypes of FTD, which display different symptoms, are also defined by gnarled clumps of TDP-43 protein and tau fibrils, respectively.

But in about 10 percent of FTD cases no such protein has been identified. The lumps were visible, but no one knew what they were made of.

Researchers suspected a protein called FUS because of the overlap between FTD and ALS, but no genetic mutations in FUS had been found in FTD cases that suggested the misfolded protein was to blame.

To see it better, Ryskeldi-Falcon, Stephan Tetter, a protein scientist at MRC-LMB, and their colleagues extracted protein samples from the brain tissue of four patients who had died of FTD and donated their brains for research.

When Tetter imaged the protein samples using cryo-electron microscopy, a technique that bombards individual flash-frozen proteins with electrons to reveal their shape, a unique structure emerged.

Panel of four black and white images showing proteins with exactly the same shape.
The structure of aggregated proteins found in four patient samples, revealed by cryo-electron microscopy. (Tetter et al., Nature2023)

It wasn’t until they sequenced those proteins, putting together the building blocks that give shape to any protein, that Tetter and his colleagues realized the protein was not FUS; It was another protein from the same protein family called TAF15.

“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,” says Tetter.

While there is much more to understand about TAF15 and the results of this study need to be validated in more patient samples, it is good news for the 10 percent of people with this unusual subtype of FTD.

The finding puts scientists on a path of discovery that began nearly 40 years ago for Alzheimer’s disease, and about a quarter-century ago for Parkinson’s disease, when researchers unraveled which proteins formed the toxic clumps in each disease.

However, that road is long and bumpy, riddled with setbacks and obstacles.

In the case of Alzheimer’s disease, a series of disappointing clinical trials punctuated by some interesting but uncertain advances, and explosive research that calls into question the reigning theory about the disease’s causes, have brought the field to a critical juncture.

It’s still early days for TAF15 and FTD, and we’ll have to see how the research develops.

The study has been published in Nature.



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