A range of neurodegenerative diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are caused by the build-up of abnormal, misfolded tau proteins in the brain. Researchers have identified potential methods to disrupt this process by targeting ‘sticky’ sites on the mutated tau protein, which can prevent the misfolding and spreading of neurofibrillary tangles.
A spectrum of neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are due to the accumulation of abnormal, misfolded tau proteins in the brain. Scientists have now found potential ways to interrupt this process by targeting ‘sticky’ sites along the long form of mutated tau, preventing the misfolding and spreading of the neurofibrillary tangles. <p>A group of researchers at UC Santa Barbara has discovered potential methods to stop the formation of abnormal, misfolded tau proteins in the brain by targeting the “sticky” sites along the long form of mutated tau. This could prevent the misfolding and spreading of the neurofibrillary tangles. UCSB neuroscientist Kenneth S. Kosik, along with chemistry professors Songi Han, Joan-Emma Shea, and chemical engineering professor Scott Shell, presented their findings in the Proceedings of the National Academy of Sciences. This study is a collaboration of biology and chemistry at a molecular level.The researchers have gained valuable insights into how pathological tau spreads. They believe that this understanding could potentially lead to therapeutic interventions capable of disaggregating tau or preventing its accumulation in its long form.
A sticky hairpin
Tau is a crucial structural protein in the brain, providing cells with shape and stability, and enabling the transportation of essential nutrients. However, if it mutates and misfolds, it can become sticky and tangled. Additionally, this misfolding error can serve as a template for incorrect instructions, causing normal tau proteins to misfold and accumulate.The condition affects wide areas of the brain, causing disruptions in brain functions. The specific areas in the brain where these neurofibrillary tangles develop vary between different neurodegenerative disorders.
There are two specific forms of tau that are the starting point for a category of neurodegenerative diseases known as tauopathies, with Alzheimer’s being the most well-known. Tau comes in both a short “three-repeat” version and a longer “four-repeat” version, with the latter being the focus of this research. Tauopathies, such as FTD, PSP, and CBD, are much less common than Alzheimer’s, and are exclusively 4R tauopathies.neurodegenerative diseases, including Alzheimer’s, can be linked to the 3R form or a combination of 3R and 4R tau. The research findings focus on diseases that accumulate 4R tau. The research team used advanced techniques such as transmission electron microscopy and molecular dynamics simulations, along with in-vitro experiments involving cell cultures, to understand the conditions that lead to the misfolding, templating, and aggregation of pathological 4R tau. Kosik stated that tau folds uniquely in each of these diseases.The 4R tau contains a unique hairpin structure, which includes a sticky segment called PHF6 that can bind and stack up other tau proteins into large aggregations. Creating conditions for tau propagation in cell culture could be a way to interfere with this sticky site, which serves as a high throughput system for discovering compounds that may be able to prevent tau aggregation. For example, a single amino acid substitution adjacent to the sticky region was found to be enough to prevent tau aggregation.The researchers found that certain nanobodies synthesized from the blood of camelids were able to bind to the PHF6 region, which inhibited the aggregation of tau. This suggests that the region encompassing the hairpin segment of 4R tau is the key area to target for potential therapies. However, the researchers still have a lot of work to do in order to develop and obtain approval for targeted therapeutics that can inhibit the formation of the neurofibrillary tangles associated with tauopathies.The paper presents potential methods for stopping the accumulation of mutant tau. Lead author Andrew Longhini and the postdoctoral researcher were credited by Kosik for their significant contributions to the ideas and experiments reported. The project also involved the work of graduate students Austin DeBose and Samuel Lobo in engineering protein interactions and computational analysis. Kosik expressed amazement at the interdisciplinary nature of the project and highlighted the importance of ongoing testing in animal models.The project has the potential to advance research on certain types of neurodegenerative diseases, offering potential insights into therapies for 3R Pick’s disease and Alzheimer’s disease. Kosik, the lead researcher, is hopeful about the possibilities. The research was supported by the Keck Foundation.
