In many neurodegenerative diseases, misfolded proteins accumulate in the brain, gradually disrupting the functioning of neurons. One of these defective proteins is tau. Its abnormal folding leads to the formation of clumps that disrupt proper brain function, leading to various pathologies. These are called tauopathies, the most well-known of which is Alzheimer's disease.
To understand how a tau protein can fold defectively, an American research team chose to study a simplified version. In a study published on April 28, 2025, researchers from Northwestern University and the University of California, USA, explain how they synthesized a simpler fragment of the tau protein that behaves like a prion.
A mini-fragment to mimic the disease
Published in the journal Proceedings of the National Academy of Sciences, the study reveals the creation of a synthetic fragment of the tau protein. Named jR2R3, it consists of only 19 amino acids. When it folds abnormally, it is able to change the conformation of other "normal" jR2R3 fragments that come into contact with it. The misfolded fragments then assemble into stacks called fibrils, in the same way that the tau protein accumulates in the brain.
This behavior of proteins that "zombify" their counterparts by modifying their folding is reminiscent of that of prions. However, it is not exactly identical. True prions are proteins called PrP that undergo misfolding and abnormal aggregation, notably causing “mad cow disease.” (see the box below, editor's note), explains Songi Han, a chemistry professor at Northwestern University who led the study. They are caused, in one way or another, by ingesting the “bad” protein, and then their aggregation spreads throughout the body.”
There " disease of there cow crazy " is the nickname for a prion disease: bovine spongiform encephalopathy. The accumulation of misfolded PrP proteins makes the brain tissue of cows spongy, causing neurological disorders. In the 1990s, an epidemic of mad cow disease began in England when farmers fed cattle with meal made from ground animal carcasses. Since 1996, more than 200 cases of humans infected by meat from diseased cows have been recorded, including 27 in France. The crisis resulted in the banning of animal meal and the culling of millions of cattle.
The aggregation of tau protein in the brain is similar to that of PrP, but it is not caused by the ingestion of a defective protein. It is a much slower process developing over several decades, making tauopathies progressive diseases for which there is currently no diagnosis or therapeutic approach. A similar process also takes place in the neurons of patients with Parkinson's disease, with the accumulation of another protein,alpha-synuclein.
Typically, fibrils are recovered from brain samples of deceased patients, making it difficult to study tauopathies. The researchers therefore wanted to synthesize a small protein fragment capable of forming fibrils like a tau protein.The novel idea is to first form a mini prion element, before later building the complete fibrillar model of the disease., summarizes Songi Han. These mini-prion models can already be used to develop diagnostic or therapeutic strategies.”
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The Amazing Role of Water
To study the folding deficiency, the jR2R3 fragment is unique in that it contains a mutation: P301L. This means that in the amino acid chain, at position 301, an amino acid called proline is replaced by another called leucine. This is a mutation widely used to model Alzheimer's disease. It destabilizes the protein's structure, facilitating its transition to a conformation that favors its prion-like behavior.
The study of jR2R3 fragments with the P301L mutation thus reveals a surprising mechanism: water plays an important role in its folding. Around the site of the mutation, water molecules reorganize in a very localized manner, thus promoting protein aggregation. In other words, the structured water acts as a kind of cement, fixing the protein strands in an ordered architecture before they propagate.
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In the future, mutations other than P301L will be studied on protein fragments such as jR2R3. This will help us better understand the specificities of each neurodegenerative disease involving the tau protein. With new tools for studying tauopathies, researchers may be able to develop better tools for diagnosing these pathologies and therapeutic avenues for curing them.
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