The transformation of the tau protein from a necessary, harmless protein that plays a vital role in our brain's normal functioning to the harmful neurofibrillary tangles characteristic of neurodegenerative diseases such as Alzheimer's is not fully understood by scientists.
However, UC Santa Barbara researchers have developed a new approach that enables them to observe and regulate the process in real time. The method involves using low-voltage electricity to mimic the natural signals that cause the protein to fold and accumulate, both in its normal brain function and in the uncontrolled process that leads to fatal illnesses.
Tau Protein Changes
According to an article in the Journal of Biological Chemistry, Daniel E. Morse, a Distinguished Professor Emeritus of Biochemistry and Molecular Genetics and the senior author of the study, stated that this technique offers scientists a new way to induce and observe the active modifications in the protein as it shifts from a beneficial to a harmful form, as reported by Newsdrum.
Eloise Masqulier, the lead author of a team consisting of students, researchers, and faculty from molecular biology, chemistry, and engineering (including Esther Taxon, Sheng-Ping Liang, Yahya Al Sabeh, Lior Sepunaru, and Michael J. Gordon), has stated that this approach has broad applicability in identifying molecules and conditions that govern the various paths of assembly in numerous, albeit related, amyloid diseases.
Typically, the tau protein exists as a soluble protein that initially adopts a relaxed, elongated structure resembling a strand of yarn. In reaction to a stimulus, tau proteins contort and gradually join together, allowing them to attach to small, cylindrical structures called microtubules that uphold the neurons' shape and transport essential molecules and nutrients within the cells. In abnormal circumstances, the signal causes the protein to accumulate excessively, creating insoluble amyloid filaments that develop into neurofibrillary tangles within the neurons, hindering their operations and ultimately leading to their demise.
Patient with Alzheimer's disease.
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Novel Technique Detecting Tau Changes
Medical Xpress mentioned that by utilizing their novel technique with the tau core fragment (a peptide), the researchers could witness and evaluate a crucial threshold between the typical, reversible folding and assembly process and the non-reversible, pathological aggregation that produces tau-related neurodegenerative disorders. The scientists elicited and fine-tuned the tau-peptide's folding in their laboratory experiments by generating an electrical potential of less than a volt to simulate hyperphosphorylation, a signal that induces disease. The folding and progressive assembly process of amyloid-like filaments were disclosed using spectroscopic methods.
In contrast to other methods of observing protein folding and assembly, such as X-ray diffraction or cryo-electron microscopy, which provide static snapshots of the processes at a specific moment in time, the new electrochemical approach enables users to observe and analyze the intricate, progressive dynamics of the folding and assembly in real-time, allowing direct observations of the crucial, initial steps in these processes. Furthermore, because the electrical stimulus closely resembles the natural signal that initiates the process, the method allows for direct observation of these processes without needing auxiliary molecules, unlike most prior methods used to investigate tau and its core peptide.
The researchers also state that the technology can function as a tool to expedite the identification and testing of drugs and antibodies with potential usefulness in preventing or treating Alzheimer's and other amyloid diseases. Morse noted, "By having the ability to initiate and adjust the process as we desire, we can utilize this system to determine which molecules may be capable of intercepting or obstructing specific stages of folding and assembly."
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