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Disease Mechanisms-Pick's Disease
Electron Cryo-Microscopy Identifies Novel Tau Protein Fold in Pick's Disease

ARTICLE IN BRIEF

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DR. WILLIAM SEELEY: “As scientists solve the detailed structures of the many disease proteins, a host of new opportunities will emerge. Understanding chemical structure will enable rational design of new diagnostics, such as more specific molecular PET ligands, as well as targeted therapeutics, such as small molecules.”

Using electron cryo-microscopy, a research team was able to visualize structures of tau filaments with high resolution and to show that distinct Alzheimer's and Pick folds of assembled tau exist.

Scientists used a powerful technique — electron cryo-microscopy — to identify a novel tau protein fold in autopsy tissue from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia, that is structurally different from the fold seen in the tau tangles in Alzheimer's disease.

These structural differences in tau filaments in human brain diseases may shed new light on how abnormal protein assemblies regulate the expression and buildup of the toxic protein and lead to specific phenotypes, said the authors of the study published in September in Nature. The finding could also help in developing biomarkers to diagnose these different conditions, and possibly in designing novel treatments.

Six tau isoforms have been identified in the normal human brain: three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau), they explained. All six are found in the tau deposits in the Alzheimer's brain. Patients with Pick's disease have only three of the six isoforms (3R tau) in their deposits. Other tau-based diseases have filaments that can be either 3R or 4R, or both.

“We have known that different tau isoforms assemble in these diseases, so the structures of tau filaments were bound to not be the same, but we were surprised to see how big the differences were,” said the senior author of the paper, Michel Goedert, MD, PhD, program leader at the Medical Research Council Laboratory (MRC) of Molecular Biology and honorary professor at the University of Cambridge in the UK.

The new technique, which involved collaboration with Sjors Scheres, PhD, an MRC structural biologist who developed a widely-used software program for electron cryo-microscopy, allowed the scientists to visualize the structures of these filaments with high resolution and to show that distinct Alzheimer's and Pick folds of assembled tau exist.

STUDY METHODS, FINDINGS

Dr. Goedert, MRC postdoctoral researcher Benjamin Falcon, PhD, and their colleagues obtained autopsied frozen brain tissue from a patient with a clinical and neuropathogic diagnosis of Pick's disease, concentrated and froze the semi-purified filamentous tau; and then fired electrons at the sample. A powerful microscope detected the signals. With the help of computers and modelling, they obtained a high-resolution structure of tau filaments. All the human tissues characterized was provided by Bernardino Ghetti, MD, professor of pathology and laboratory medicine at Indiana University School of Medicine, a co-author of the study.

The neuropathological exam confirmed severe frontotemporal lobar degeneration with many Pick bodies composed of 3R tau without phosphorylation of Ser262. In this patient, they observed severe atrophy of the anterior frontal and temporal lobes of the cerebral cortex.

They compared what they saw with human tissues from a patient with Alzheimer's disease that they had previously used electron cryo-microscopy to study. (They had described that tissue in a paper in Nature last year.)

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DR. JOHN Q. TROJANOWSKI: “This finding may provide important clues on how to develop imaging ligands to identify different tau pathologies.”

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HIGH-RESOLUTION cyro-electron microscopy map of the narrow Pick filaments with the atomic model of the Pick fold overlaid. (B) Schematic view of the Pick fold.

The filaments from the patient with Pick's disease, which consisted of Lys254-Phe378, were folded differently than the filaments identified in the AD brains, they found.

“The observed tau fold in the filaments of patients with Pick's disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer's disease,” the authors wrote in the paper. “Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.”

The high resolution allowed them to build an atomic model of the Pick fold. They can literally see how the strands are stacked and connected by turns and arcs “and packed in a hairpin-like fashion,” Dr. Goedert explained. They showed the molecules at each turn of the folds, and the directions of the protein chains laid out in the structure.

The research team went on to study the binding of repeat-specific antibodies to tau filaments from the frontotemporal cortex of nine patients who died with sporadic Pick's disease. They identified a specific signal that was unique to the Pick fold.

“It could be possible to molecularly alter the structure to treat the disease,” Dr. Goedert added.

“Our results also suggest that single, disease-specific folds may exist in tauopathies with the same tau filament isoform composition, such as progressive supranuclear palsy and corticobasal degeneration, since identical tau sequences can adopt more than one fold.”

Dr Goedert said that the different conformers of tau filaments may well trigger the clinical phenotypes. “We have been looking at the end stages of disease,” he explained. “We hope that by determining additional high-resolution structures of tau filaments from the brain, we will be able to design experiments that are aimed at understanding the mechanisms that cause tau assembly.”

EXPERT COMMENTARY

“This study represents an important moment in the history of neurodegeneration research,” said William Seeley, MD, professor of neurology and pathology at University of California, San Francisco, and director of the Neurodegenerative Disease Brain Bank at the UCSF Memory and Aging Center.

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DR. MICHEL GOEDERT: “We have known that different tau isoforms assemble in these diseases, so the structures of tau filaments were bound to not be the same, but we were surprised to see how big the differences were.”

“As scientists solve the detailed structures of the many disease proteins, a host of new opportunities will emerge. Understanding chemical structure will enable rational design of new diagnostics, such as more specific molecular PET ligands, as well as targeted therapeutics, such as small molecules.”

“For the sporadic tauopathies, the still-burning question is why these protein misfolding events occur in the first place, but it feels much easier to address why now that we are learning more about what,” he added.

“This finding may provide important clues on how to develop imaging ligands to identify different tau pathologies,” said John Q. Trojanowski, MD, PhD, professor of geriatric medicine and gerontology in the department of pathology and laboratory medicine at the University of Pennsylvania School of Medicine. “They should help explain conformational differences in the Pick's pathology and facilitate drug discovery [in answer to the question]: Do the differences in shape explain strains that exist for different pathologies and phenotypes that we see?”

LINK UP FOR MORE INFORMATION:

• Falcon B, Zhang W, Murzin AG, et al. Structures of filaments from Pick's disease reveal a novel tau protein fold https://www.nature.com/articles/s41586-018-0454-y. Nature 2018; 56(7721): 137–140.
• Fitzpatrick AWP, Falcon B, He S, et al. Cryo-EM structures of tau filaments from Alzheimer's disease https://www.nature.com/articles/nature23002. Nature 2017; 547:185–190.