Researchers at the Massachusetts Institute of Technology (MIT) have made a significant advance in understanding the structure of Tau proteins, which are critical in the development of Alzheimer’s disease. The study reveals the complex “fuzzy coat” that surrounds these proteins, a finding that could assist in developing therapies to combat Tau buildup in the brain.
Tau proteins are known to misfold and clump together, forming tangles that are a hallmark of Alzheimer’s. According to the new study, the fuzzy coat, which comprises disordered segments, plays a crucial role in how Tau proteins interact with other molecules. The findings were published in the Journal of the American Chemical Society on March 15, 2024, with lead author and MIT graduate student Jia Yi Zhang indicating that understanding this structure could inform future drug design.
Characterizing the Fuzzy Coat
In healthy individuals, Tau proteins stabilize microtubules, which are essential for maintaining cell structure. However, when these proteins misfold, they contribute to neurodegenerative diseases, including Alzheimer’s and frontotemporal dementia. The challenge of studying Tau proteins lies in the fact that approximately 80 percent of the protein resides in the fuzzy coat, which is highly disordered and difficult to analyze using conventional techniques like cryoelectron microscopy and X-ray crystallography.
The research team, led by Mei Hong, a professor of chemistry at MIT, utilized nuclear magnetic resonance (NMR) spectroscopy to explore the entire Tau protein structure. This innovative approach allowed them to magnetize protons within the more rigid segments of the protein and track how this magnetization transferred to the more mobile, disordered segments. The result was a comprehensive view of the interactions between the rigid core and the fuzzy coat.
Insights into Protein Dynamics
The findings revealed that the overall structure of the Tau protein resembles a burrito, where multiple layers of the fuzzy coat envelop a rigid core made of folded protein strands known as beta sheets. The researchers categorized the segments of the fuzzy coat into three groups based on their mobility. They discovered that the most dynamic regions, rich in the amino acid proline, were located in the outermost layer. Interestingly, these prolines, previously thought to be partially immobilized, were found to be highly mobile, interacting dynamically with the core.
This structural insight is critical because it sheds light on how Tau proteins can form tangles in the brain. Misfolded Tau proteins may recruit normal Tau proteins, prompting them to adopt an abnormal structure. The study suggests that the fuzzy coat’s design may facilitate the addition of normal Tau proteins to the ends of existing fibrils, potentially leading to longer aggregates.
The research team now aims to further investigate whether they can stimulate normal Tau proteins to assemble into fibrils characteristic of Alzheimer’s disease, using misfolded Tau proteins derived from Alzheimer’s patients as a template. This research was funded by the National Institutes of Health, marking a hopeful step toward understanding and potentially combating the progression of Alzheimer’s disease.
