Scientists have identified the protein that forms the clumps characteristic of a type of early-onset dementia for which no firm suspect was known until now.
UK researchers who made the discovery say the breakthrough transforms understanding of the molecular basis of frontotemporal dementia (FTD), the second most common form of dementia after Alzheimer’s, with symptoms usually appearing earlier: between 40 and 50 years. It is the disease from which the American actor Bruce Willis also suffers.
People diagnosed with FTD show changes in behavior, personality, language and movement caused by the slow degeneration of the frontal and temporal lobes of the brain.
Memory problems may occur later as the disease spreads to other regions of the brain.
But without knowing the true makeup of the protein deposits that form the clumps (neurofibrillar tangles/tangles) seen in some of the rarer cases of FTD, researchers didn’t have many targets to explore for potential therapies.
“This is a rare discovery of a new member of the small group of proteins known to aggregate in neurodegenerative diseases,” says Benjamin Ryskeldi-Falcon, a specialist at the UK MRC’s Laboratory of Molecular Biology (LMB), who led The study, in a statement.
Proteins that form clumps are what unites neurodegenerative diseases and what distinguishes them.
Just as beta-amyloid and tau proteins form such “tangles” in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, SOD1 protein in amyotrophic lateral sclerosis (ALS), and Huntington’s, the eponymous protein that gives Huntington’s disease its name, form sticky clumps of different forms in diseased brain tissue.
Different subtypes of FTD, which present different symptoms, are also defined by clumps of TDP-43 protein and tau fibrils, respectively.
But in about 10% of FTD cases no such protein has been identified. The lumps were visible, but no one knew until now what they were made of.
The researchers suspected a protein called FUS, because of the similarity between FTD and ALS, but no genetic mutations in FUS were found in FTD cases to suggest that this was the misfolded protein to blame.
To find an explanation, the UK team extracted protein samples from the brain tissue of four patients who had died of FTD and who had donated their brains for research.
When the researchers imaged the protein samples using cryo-electron microscopy – a technique that bombards individual proteins instantly frozen to reveal their shape – they identified only one unique structure.
Only after sequencing these proteins, breaking them down into the constituent elements that make up any protein, did the team discover that it was not the FUS protein, but another one 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 the structure of this protein was not known,” says Stephan Tetter, protein researcher at MRC-LMB.
Although there is still much to learn about TAF15, and the results of this study need to be validated in more patient samples, it is welcome news for the 10% of people with this unusual subtype of FTD.
With this discovery, scientists align themselves with the line of research started almost 40 years ago for Alzheimer’s disease and now a quarter of a century for Parkinson’s diseasewhen researchers discovered which proteins form the toxic clumps in each disease.
This path is a long road, strewn with failures and obstacles. In the case of Alzheimer’s disease, a series of disappointing clinical trials, interspersed with exciting advances, but uncertainand an explosive research that question the dominant theory of disease causes have brought this field to a critical juncture.
The authors say that it is still too early to draw major conclusions related to the TAF15 protein and frontotemporal dementia, and that further research is needed in this direction.
However, knowing the identity and basic structure of these filaments in this rare form of early-onset dementia is vital for the development of early diagnostic tests and drugs to combat their formation.
The study was published Wednesday in the journal Nature.
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2023-12-09 06:30:00
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