A team of MIT scientists have provided insights into the formation of harmful Tau protein filaments, typically associated with neurodegenerative diseases. The researchers found that the Tau protein’s propensity to form detrimental filaments increases when its ends are removed and its flexibility contributes to the varying shapes of these filaments. Additionally, a sequence of amino acids has been identified that could serve as a drug target to hinder filament formation.
The study reveals that the Tau protein, when truncated, is more prone to creating the adhesive filaments often observed in the brains of Alzheimer’s patients.
Alzheimer’s, along with many other neurodegenerative diseases, feature tangled proteins known as Tau fibrils. Through their latest research, MIT chemists have delved into how these fibrils are formed, and pinpointed a possible drug target that could disrupt this formation process.
The researchers found that a section of the Tau protein is unexpectedly flexible, contributing to the fibrils’ ability to adopt diverse shapes. This increased propensity for filament formation occurs when the Tau protein’s ends are removed.
MIT professor of chemistry, Mei Hong, who is also the senior author of the study, explained that this protein truncation occurs relatively early in Alzheimer’s disease, accelerating an unwanted aggregation process.
In brains impacted by Alzheimer’s, abnormal Tau protein clusters amass and form tangles within neurons, damaging nerve cells’ synaptic communication. The study identifies a sequence of amino acids that helps the Tau protein bend in multiple directions, offering a promising drug target to thwart Tau tangle formation.
Nadia El Mammeri, a postdoc at MIT, is the lead author of the study, published on July 14 in Science Advances. Pu Duan and Aurelio Dregni, also postdocs at MIT, contributed to the paper.
In a healthy brain, Tau proteins bind to and stabilize microtubules. This protein comprises four slightly differing repeating subunits, known as R1, R2, R3, and R4. In the brains of individuals with Alzheimer’s and other neurodegenerative diseases, abnormal Tau forms filamentous tangles.
The researchers focused on the Tau protein’s central core where rigid beta sheets are formed. This core is enclosed by flexible segments forming a protective “fuzzy coat”. In Alzheimer’s disease, these end segments are often lost, causing the rigid core to form filaments more readily. This suggests a protective role of the fuzzy coat against neurodegenerative disease.
Hong explained that the removal of these segments expedites the formation of fibrils, pointing to a protective role of the fuzzy coat in natural proteins.
Furthermore, the researchers discovered that the R3 repeat is notably rigid, while the R2 repeat has more flexibility and can adopt different forms based on environmental factors such as temperature.
Under varying conditions, R2 can exist in straight or hinged forms. This conformational flexibility may account for slight structural differences observed in Tau proteins associated with different diseases, including Alzheimer’s, corticobasal degeneration, and argyrophilic grain disease.
Within the flexible R2 repeat, a sequence of six amino acids was identified that makes the structure more adaptable than other segments. This region could provide a viable target for drugs that would inhibit Tau fibril formation, Hong suggested.
The scientists plan to investigate whether they can create Tau structures that closely resemble those found in the brains of patients with Alzheimer’s and other neurodegenerative diseases, by truncating the protein at specific points or adding disease-associated chemical modifications.
The study, titled “Amyloid fibril structures of tau: Conformational plasticity of the second microtubule-binding repeat” by Nadia El Mammeri, Pu Duan, Aurelio J. Dregni, and Mei Hong, was published on July 14, 2023, in Science Advances. The research was funded by the National Institutes of Health and an NIH Ruth L. Kirschstein Individual National Research Service Award.
Table of Contents
Frequently Asked Questions (FAQs) about Tau protein tangles
What did the MIT researchers discover about Tau protein?
The MIT researchers found that Tau protein, often associated with neurodegenerative diseases, forms harmful filaments more easily when its ends are truncated. Additionally, its flexibility contributes to the diversity of filament shapes. They also identified a specific sequence of amino acids that could serve as a drug target to prevent these filaments from forming.
How is the formation of Tau protein filaments related to Alzheimer’s disease?
In the brains of individuals with Alzheimer’s disease, Tau proteins form sticky filaments that aggregate into tangles within neurons. This process harms synaptic communication between nerve cells, contributing to the progression of Alzheimer’s disease.
What are the possible drug targets identified in the study?
The researchers pinpointed a sequence of amino acids that helps the Tau protein bend in multiple directions. This region, particularly within the flexible R2 repeat, could potentially be targeted by drugs to inhibit the formation of Tau fibrils, and hence slow down the progression of neurodegenerative diseases.
What is the significance of the “fuzzy coat” in the Tau protein?
The “fuzzy coat,” formed by flexible end segments of the Tau protein, slows down the formation of harmful filaments. When these end segments are removed, a process that often happens in Alzheimer’s disease, the protein forms filaments much more readily, indicating a protective role of the fuzzy coat against neurodegenerative disease.
What future research do the MIT scientists plan to conduct?
The MIT researchers plan to generate Tau structures that more closely match those found in the brains of patients with Alzheimer’s and other neurodegenerative diseases. This involves truncating the protein at specific points or adding disease-associated chemical modifications. This could provide further insights into the structural formation and progression of these diseases.
More about Tau protein tangles
- MIT News
- Science Advances
- National Institutes of Health (NIH)
- Information on Alzheimer’s Disease
- Overview of Tau Proteins
