Buried deep in the brain, a protein that normally helps sustain nerve cells can be a source of trouble.
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that → bury → trouble
When tau proteins change from their normal shape, they can start to cling together, creating tangled structures linked to Alzheimer’s disease and other forms of dementia, an online report from Northwestern University says.
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report → change → University
Scientists have long grappled with the question of how these misshapen proteins can persuade healthy ones to do the same.
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proteins → grapple → same
Now, researchers at Northwestern University may have discovered a key vulnerability in that process, a single molecular hotspot that could offer a new target for future treatments.
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that → discover → treatments
Finding the trigger for tau clumping
The study was conducted by scientists at Northwestern University in collaboration with colleagues at the University of California, Santa Barbara, who investigated the misfolding of tau proteins and their assembly into long, threadlike structures called fibrils.
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who → find → structures
The research, published in the Proceedings of the National Academy of Sciences, identified that there is a particular region of tau that seems to dominate in triggering the process.
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that → publish → process
Normally, tau proteins are flexible and have no fixed structure.
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proteins → have → structure
But if they misfold they can latch onto existing fibrils and adopt the same abnormal shape.
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they → misfold → shape
As more proteins attach to the growing structure, the fibrils become longer and may help create neurofibrillary tangles within neurons.
Such deposits are characteristic of several neurodegenerative diseases such as Alzheimer’s disease and frontotemporal dementia.
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deposits → attach → disease
They can interfere with communication between nerve cells and contribute to the damage that occurs with cognitive decline.
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that → interfere → decline
The surprising role of water
The researchers found that the hotspot is in a hydrophobic part of tau — one that doesn't readily interact with water.
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that → find → water
But proteins are in a watery cellular environment, so these regions still need to be protected from their surroundings.
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regions → need → surroundings
The water molecules form a protective layer or cap around the hotspot, but it is a dynamic layer.
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it → form → hotspot
Researchers found that these water structures help determine where two tau proteins come together.
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proteins → find → ?
When hotspots come together, the water around them is released.
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water → come → them
The energy released by this process stabilizes the interaction, allowing the incoming tau protein to align with an existing fibril and assume its misfolded shape.
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protein → release → shape
The report found that tau proteins stack in a uniform order to allow for continued growth of the fibrils.
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proteins → find → fibrils
The newly identified hotspot appears to help coordinate that process, offering a molecular explanation for how an initially disordered protein can build an orderly, expanding structure.
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protein → identify → structure
When the hotspot is blocked, growth stops
To determine whether the hotspot was important, the team attached a chemical tag to the region they had found.
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they → block → region
In laboratory experiments, this intervention blocked the growth of tau fibrils.
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intervention → block → fibrils
The researchers also identified two other areas, away from the hotspot.
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researchers → identify → hotspot
These interventions did not stop fibril growth, adding weight to the idea that the site identified plays a particularly important role in the process.
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site → stop → process
Thus, disrupting this interaction could eventually be a way to stop misfolded tau from dragging other proteins along.
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disrupting → disrupt → proteins
But the experiments were conducted in the lab, and more research will be needed to determine if the approach can be safely and effectively used in living organisms.
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approach → conduct → organisms
A shortcut for future therapies perhaps
If a specific molecular target can be identified, researchers can hone in on potential treatments, rather than trying to block tau aggregation across the entire protein.
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researchers → identify → protein
The discovery could also lead to the development of diagnostic tools and synthetic tau fibrils that more accurately mimic disease-related structures for laboratory research.
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that → lead → research
Scientists have struggled to create dependable models of these rogue proteins, making it difficult for them to study how various tau-related diseases progress and to test possible treatments.
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diseases → struggle → treatments
The Northwestern-led study shows how a specific region helps misfolded tau propagate, identifying a more precise starting point for future studies.
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tau → lead → studies
The discovery is not a treatment for Alzheimer’s, yet, but it finds a potential weakness in one of the molecular processes associated with neurodegeneration, a small target that could have widespread implications for research into diseases that remain difficult to treat.
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that → find → diseases
The Aporia
