Structure of tau filaments in patients with Pick's disease determined

August 30, 2018 by Bob Yirka, Medical Xpress report
Tau Protein. Credit: Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute

A team of researchers with the MRC Laboratory of Molecular Biology in the U.K. and Indiana University School of Medicine in the U.S. has determined the structure of tau filaments in patients with Pick's disease. In their paper published in the journal Nature, the group describes the technique and technology they used to discover the shape of the folds in the brain and what they found.

Neurological diseases are often characterized by misfolded tau proteins in the brain that lead to the destruction of neurons. Prior research has led to the discovery that there are six tau shapes in the human brain, and all of them are essential for normal neuronal activity. For unknown reasons, these proteins sometimes fold improperly, which leads to a cascading effect in which more become misfolded—such cascades are referred to as filaments, and the cascading effect is what leads to degeneration of neurons, and in most patients, death from neurological disease. The researchers with this new effort have been working to determine the structure of the misfolds involved in such diseases, hoping to an understand why proteins misfold, and perhaps find a way to stop it from happening. Recently, they announced that they had determined the structure of tau filaments associated with Alzheimer's disease. In this new effort, they have now done the same with Pick's disease—a degenerative neurological disease that results in destruction of neurons in the .

Tau proteins can have a structure made up of either three or four microtubule-binding repeats, and filaments can have either or both structures. The researchers discovered that such filaments associated with Pick's disease had just three repeats, and that they were novel in shape and distinct from those found in patients with Alzheimer's disease. The technique involved using electron cryomicroscopy, in which samples were cooled to cryogenic temperatures and then examined with an electron microscope. The finding offers evidence to back up a theory that suggests the differences in are likely due to differences in structures.

Explore further: Scientists uncover the structure of tau filaments from Alzheimer's disease

More information: Benjamin Falcon et al. Structures of filaments from Pick's disease reveal a novel tau protein fold, Nature (2018). DOI: 10.1038/s41586-018-0454-y

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies seem to spread through specific neural networks in each disease, with short filaments having the greatest seeding activity. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau). In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations. Such conformers may give rise to different neuropathological phenotypes, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau. Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer's disease, establishing the existence of conformers of assembled tau. 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. 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.

Related Stories

Scientists uncover the structure of tau filaments from Alzheimer's disease

July 6, 2017
Researchers at the MRC Laboratory of Molecular Biology (LMB) have, for the first time, revealed the atomic structures of one of the two types of the abnormal filaments which lead to Alzheimer's disease. Understanding the ...

Study identifies chaperone protein implicated in Parkinson's disease

August 13, 2018
Reduced levels of a chaperone protein might have implications for the development and progression of neurodegenerative diseases such as Parkinson's disease and Lewy body dementia, according to new research from investigators ...

Overlapping mechanisms in HIV cognitive disorders and Alzheimer's disease

April 9, 2018
A protein involved in Alzheimer's disease (AD) may be a promising target for treating neurological disorders in human immunodeficiency virus (HIV) patients, suggests a study published in JNeurosci of rat neurons and brain ...

Rare, lethal childhood disease tracked to protein

April 29, 2013
A team of international researchers led by Northwestern Medicine scientists has identified how a defective protein plays a central role in a rare, lethal childhood disease known as Giant Axonal Neuropathy, or GAN. The finding ...

Recommended for you

MDMA makes people cooperative, but not gullible

November 19, 2018
New research from King's College London has found that MDMA, the main ingredient in ecstasy, causes people to cooperate better—but only with trustworthy people. In the first study to look in detail at how MDMA impacts cooperative ...

How the brain switches between different sets of rules

November 19, 2018
Cognitive flexibility—the brain's ability to switch between different rules or action plans depending on the context—is key to many of our everyday activities. For example, imagine you're driving on a highway at 65 miles ...

Mutation that causes autism and intellectual disability makes brain less flexible

November 19, 2018
About 1 percent of patients diagnosed with autism spectrum disorder and intellectual disability have a mutation in a gene called SETD5. Scientists have now discovered what happens on a molecular level when the gene is mutated ...

Signal peptides' novel role in glutamate receptor trafficking and neural synaptic activity

November 19, 2018
Glutamate is the major excitatory neurotransmitter in the brain, and the postsynaptic expression level of glutamate receptors is a critical factor in determining the efficiency of information transmission and the activity ...

Scientists identify novel target for neuron regeneration and functional recovery in spinal cord injury

November 19, 2018
Restoring the ability to walk following spinal cord injury requires neurons in the brain to reestablish communication pathways with neurons in the spinal cord. Mature neurons, however, are unable to regenerate their axons ...

Study explains behavioral reaction to painful experiences

November 19, 2018
Exposure to uncomfortable sensations elicits a wide range of appropriate and quick reactions, from reflexive withdrawal to more complex feelings and behaviors. To better understand the body's innate response to harmful activity, ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.