Unveiling Mechanisms to Block Tau Aggregation

The buildup of aberrant, misfolded tau proteins in the brain is the cause of a variety of neurodegenerative illnesses, such as Fronto Temporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), and Cortico Basal Degeneration (CBD).

Targeting “sticky” locations along the long form of mutant tau, a team of researchers led by UC Santa Barbara scientists has discovered possible strategies to halt this process and stop the misfolding and proliferation of the neurofibrillary tangles.

Kenneth S. Kosik, a Neuroscientist from the University of California, said, “This is a true collaboration of biology and chemistry.

Kenneth S. Kosik, along with Chemistry Professors Songi Han, Joan-Emma Shea, and chemical engineering professor Scott Shell, published the findings in the journal Proceedings of the National Academy of Sciences.

The study presents molecular-level insights on the way pathological tau spreads, and according to the researchers, this understanding could lead toward “a therapeutic intervention potentially capable of disaggregating tau or preventing its aggregation” in the long form of tau accumulates.

A Sticky Hairpin

Tau is a crucial structural protein in the brain that provides cells with shape and stability and facilitates the movement of vital nutrients. It can get sticky and twisted as it mutates and misfolds.

Furthermore, this folding defect may serve as a model for incorrect instructions that cause normal tau proteins to misfold and accumulate, causing the illness to spread to large areas of the brain and impair brain function. The brain regions in which these neurofibrillary tangles are found vary depending on the type of neurodegenerative disease.

This class of neurodegenerative disorders, known as tauopathies, is based on two distinct types of tau, the most well-known of which is Alzheimer's disease. Tau can be created in two different formats: a brief “three-repeat” version and a lengthier “four-repeat” variant, which is the subject of this study.

Neurodegenerative illnesses can be linked to either the 3R form or, as in the case of Alzheimer's, a combination of both types of tauopathies. However, tauopathies that are much less frequent than Alzheimer's, such as FTD, PSP, and CBD, are solely of the 4R type. The findings of this study are relevant to illnesses where 4R tau builds up.

By combining sophisticated methods like molecular dynamics simulations and transmission electron microscopy with in vitro experiments using cell cultures, the research team could understand the circumstances that lead to pathological 4R tau misfolding, tau protein tagging, and aggregate.

Tau folds in a unique way in each of these diseases. One part of it folds into a hairpin structure only in the 4R tau.”

Kenneth S. Kosik, Neuroscientist, University of California

He explained that a sticky segment called PHF6 within the hairpin can bind and stack up other tau proteins into large aggregations.

However, what if tau aggregation could be induced in cell culture, and this sticky spot could be interfered with using the system?

Kosik commented, “Creating conditions for tau propagation serves as a high throughput system for the discovery of compounds that may interfere with tau aggregation.” 

For example, by weakening access to the vulnerable area of the peptide, they discovered that a single amino acid alteration along the protein next to the sticky region was sufficient to prevent tau aggregation. 

In additional studies, the researchers discovered that camelid blood was used to create nanobodies, or fragments of antibodies, which could attach to the PHF6 area and prevent tau from aggregating. Camels, llamas, and other camelid family members are examples of camelids. The area surrounding the hairpin section of 4R tau appears to be the active zone to target, regardless of the therapy.

It will take a while for tailored therapies to be created and approved to prevent the development of the neurofibrillary tangles that are a hallmark of tauopathies, according to researchers. However, the research presented in this work reveals intriguing new avenues for stopping the buildup of mutant tau. 

We would want to continue to test this technology in animal models,” Kosik said, crediting postdoctoral researcher and lead author Andrew Longhini for his “enormous contributions” to ideas and the experiments reported. On the chemistry side, the contributions of graduate student researchers Austin DeBose and Samuel Lobo were pivotal in engineering protein interactions and handling the computational workload, emphasizing the source.

Kosik said, “It is so interdisciplinary, it is amazing, I learned so much from this project.”

These results not only progress the understanding of some types of neurodegenerative diseases but also provide a starting point for the hunt for novel therapeutic targets for both the more complicated Alzheimer's disease and 3R Pick's disease. Kosik feels hopeful.

Kosik said, “We will try to apply our findings to the more complicated forms, we will get there.”

Source:
Journal references:

Longhini, ‌ A. P., et al. (2024) Precision proteoform design for 4R tau isoform selective templated aggregation. PNAS. doi.org/10.1073/pnas.2320456121.

 

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