HMN 2025: How Modified tau thwarts aggregation in neurodegenerative disease—while retaining its biological function

A designer version of the tau protein, developed by a team led by UT Southwestern Medical Center researchers, maintains its biological function while resisting aggregation, a pathological trait linked to neurodegenerative diseases called tauopathies.

These findings, reported in Structure, could lead to new treatments for conditions including Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy (CTE), and progressive supranuclear palsy.

“This is the first step toward creating a molecule that could, in principle, replace a protein that’s pathogenic (disease-causing) while still retaining its normal function,” said study leader Lukasz Joachimiak, Ph.D., Associate Professor in the Center for Alzheimer’s and Neurodegenerative Diseases and of Biochemistry and Biophysics at UT Southwestern.

Understanding tau’s role and pathology

Tau plays an essential role in cells, where it regulates assembly and stability of microtubules, protein assemblies that serve as highways to guide vesicles, organelles, and other components through cytoplasm. Tau binds to microtubules through a part of the tau protein in which a stretch of amino acids is repeated either three or four times. These versions of tau are known as 3R or 4R, respectively.

In tauopathies, tau proteins stick together, or aggregate, forming threadlike clumps that create deposits in the brain. Previous research has shown that the vast majority of tauopathies occur from aggregation of the 4R form of tau, Dr. Joachimiak explained. But why this happens—and whether it’s possible to modify tau to prevent aggregation without disrupting microtubule binding—has been unknown.

Designing aggregation-resistant tau

To answer these questions, researchers from the Joachimiak Lab and their colleagues constructed fragments of tau made of the 4R repeats and the so-called VQIVYK motif—the portion of the protein responsible for forming clumps—changing a few amino acids between these sections to mimic those found in 3R. Although fragments made without the amino acid substitutions readily aggregated in test tubes, the designed fragments did not.

A closer look revealed why: The section between the repeats and the VQIVYK motif in the designed fragments formed a rigid curve that gave them a hairpin shape, preventing them from contacting VQIVYK motifs on other fragments and forming clumps.

Further experiments confirmed that this design strategy also worked in larger pieces of tau and in cells, with the altered protein thwarting aggregation with natural 4R tau.

Implications for future therapies

Importantly, Dr. Joachimiak said, changing these amino acids didn’t affect tau’s ability to bind to microtubules, suggesting the altered protein can still perform its biological function.

“The fact that the engineered tau variants retained microtubule binding indicates it may be possible to preserve physiological function while reducing pathogenic aggregation,” he said.

Dr. Joachimiak added that his team’s future research will test whether replacing natural tau with this designer version can thwart tauopathies in animal models, a step toward crafting new treatments for neurodegenerative diseases.

“Many studies have examined tau isoforms, aggregation mechanisms, and mutations such as those associated with frontotemporal dementia,” he said.

“But few, if any, have undertaken rational design of tau variants to reduce aggregation while retaining its function as we have with this research.”

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