For the first time, scientists have published highly detailed structures of tau filaments, using cryo-electron microscopy. Tau protein filaments are mainly known for their implications in Alzheimer’s disease.
The research, published in last week’s Nature, could pave the way for gaining mechanistic insights about a wide range of neurodegenerative diseases, as well as start the process for more targeted drug development for Alzheimer’s disease.
The study was carried out by researchers from the Medical Research Council (MRC) Laboratory of Molecular Biology (UK), and Indiana University School of Medicine (US).
“This is a tremendous step forward,” says Bernardino Ghetti, one of the research team members from Indiana University. “It’s clear that tau is extremely important to the progression of Alzheimer’s disease and certain forms of dementia. In terms of designing therapeutic agents, the possibilities are now enormous.”
Alzheimer’s disease prognosis is affected by two proteins: tau and beta amyloid. Tau proteins maintain the transport systems within healthy neuronal cells of the brain. When tangles begin to form, tau collapses into filaments that interfere with normal structures and upset the ordered ‘rail-tracks’ of the transport system. These neurofibrillary tangles disrupt communication and normal cellular function.
[Read more about Alzheimer’s disease, and how tau and amyloid proteins may contribute to the disease here.]
Unraveling the structures of these tangles, and studying the changes in tau proteins from patients with Alzheimer’s disease, would significantly advance the design of better therapeutic agents.
The new research stands apart from previous endeavors in two key ways- the tau filaments were purified from a 74-year-old deceased patient previously diagnosed with Alzheimer’s disease and the research team used the rapidly advancing structural technique – Cryo-electron microscopy (cryo EM).
In previous studies, tau filaments were assembled from protomers in the lab. However, the trouble with tau filaments is that they adopt different molecular conformers. There are six isoforms of tau and their filamentous forms are implicated in different diseases, shedding some doubt on whether the lab-made filaments resemble the disease states in patients with Alzheimer’s.
“By purifying the tau filaments straight from a diseased human brain, we know that these structures are the ones relevant for Alzheimer’s disease,” explained study author Sjors Scheres to the Laboratory Equipment. “In the prion field (where amyloids form infectious protein aggregates), these different conformations are called ‘strains’. It could be that different strains of certain amyloids play different roles in different diseases.”
Sjors Scheres is a group leader at the MRC Laboratory of Molecular Biology and an expert in the field of cryo-EM. His group created RELION (Regularized LIkelihood OptimisatioN), the software that was used to statistically compute and render 3-D reconstructions of the isolated tau filaments’ structure.
“Cryo-EM was essential for this project. We have used collaborations with various groups to work on cryo-EM samples that were challenging to existing methods in order to drive methods development forward, while also learning exciting new things about biology,” said Dr. Scheres.
“Until now, the high-resolution structures of tau or any other disease-causing filaments from human brain tissue have remained unknown,” said co-author Michael Goedert, who has worked on tau and other amyloid proteins for near 30-years.
“This new work will help to develop better compounds for diagnosing and treating Alzheimer’s and other diseases that involve defective tau.”
Their collaboration has worked to the benefit of the medical research community and advanced the understanding of amyloid pathologies.
“Fitzpatrick and colleagues have paved the way for the development of new drugs designed to prevent tangle formation by deciphering the molecular structure of the tau protein filaments that make up the tangles at atomic resolution,” says David Allsop, Professor of Neuroscience at Lancaster University.
“However, there are some formidable obstacles to be overcome for this approach to be successful,” he continues. “Any tangle-acting drug must cross the blood-brain barrier to enter the brain, and must also penetrate inside nerve cells in affected brain regions. The other main problem is that tau protein has a very important function in these nerve cells. It is involved in the assembly of structures called ‘microtubules’ that transport materials along the ‘axons’ of nerve cells, and interfering with this process would be highly problematic.
“We are a long way from having an effective tau-directed drug, but the work of Fitzpatrick and colleagues is at least a step in the right direction.”
Source: Indiana University