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New method of classifying tauopathies from MRC Laboratory of Molecular Biology offers insight into neurodegenerative diseases




New insight into a range of neurodegenerative diseases has been achieved by scientists at the MRC Laboratory of Molecular Biology in Cambridge using cryo-electron microscopy.

Their work suggested a new method for classifying those diseases collectively known as tauopathies because of their link to misfolded tau proteins.

Michel Goedert. Picture: Keith Heppell
Michel Goedert. Picture: Keith Heppell

The method suggests ways of studying the similarities and differences between diseases and has also led to the identification of a new disease.

It follows a long-standing collaboration between Michel Goedert’s group in the LMB’s Neurobiology Division and Sjors Scheres’ group in the LMB’s Structural Studies Division.

Together these groups have already used cryo-electron microscopy (cryo-EM) in order to solve the structures of tau filaments from the tauopathies Alzheimer’s disease, primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), Pick’s disease and corticobasal degeneration (CBD).

The structure of tau filaments from a further eight tauopathies have now been solved by the groups, working with their long-term collaborators Bernardino Ghetti, from the Indiana University School of Medicine, and Masato Hasegawa, from the Tokyo Metropolitan Institute of Medical Science.

Tau protein is present in brain cells to help them maintain normal function. But in disease, this protein sticks together and forms filaments many molecules in length, which are toxic to the cell and lead to cell death – the process known as neurodegeneration.

Despite the fact that the folds are all made of the same protein, they lead to different diseases.

For their latest work, the group used brain tissues from neuropathologically confirmed cases of human diseases and extracted the tau filaments before determining their structures using cryo-EM, which involves flash-freezing a microscopic protein sample in a single-molecule-thick layer of vitreous ice.

Sjors Scheres. Picture: MRC Laboratory of Molecular Biology
Sjors Scheres. Picture: MRC Laboratory of Molecular Biology

This enabled them to determine the structures of tau filaments from progressive supranuclear palsy (PSP), globular glial tauopathy (GGT), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), familial British dementia (FBD), familial Danish dementia (FDD), and inherited cases with mutations +3 and +16 in intron 10 of MAPT, the microtubule-associated protein tau gene.

Sjors tells the Cambridge Independent: “The structures provide additional information for classifying tauopathies, which was previously done by clinical diagnosis and post-mortem neuropathology.”

Complementing these traditional approaches, the latest findings and the previous research suggest a new, hierarchical method to classify tauopathies, based on their filament folds.

“For example, based on their tau filament folds, CBD and AGD are more closely related to each other than CBD and PSP. This distinction was not clear from the clinical symptoms alone, which are often similar for PSP and CBD,” notes Sjors.

“In addition, by discovering a previously unobserved tau filament fold for a case that was originally diagnosed as PSP, we could suggest that this individual was suffering from a new disease. We called it Limbic-predominant Neuronal inclusion body 4R Tauopathy (LNT).”

The classification of tauopathies. Picture: MRC Laboratory of Molecular Biology
The classification of tauopathies. Picture: MRC Laboratory of Molecular Biology

What surprises him most about the findings is “the observation that the same tau protein folds up differently in the different tauopathies, and yet that all individuals with a given disease have the same tau filament structures”.

“Something highly specific must be going on in each of these diseases,” he notes.

The structure of tau aggregates, from earlier work at the LMB. The numbers refer to the sequence of tau protein, with the colours showing the same regions of tau protein. The purple circle in the CTE fold is the extra density. Image: MRC Laboratory of Molecular Biology
The structure of tau aggregates, from earlier work at the LMB. The numbers refer to the sequence of tau protein, with the colours showing the same regions of tau protein. The purple circle in the CTE fold is the extra density. Image: MRC Laboratory of Molecular Biology

Exploring the similarities and differences between the diseases, the researchers showed:

  • PSP and CBD, thought to be closely related because they are both clinically similar 4-repeat tauopathies, have tau folds that are more disparate than thought. Solving the structures of tau filaments from PSP revealed a novel three-layered fold.
  • PSP filaments are more similar to those of GGT, cryo-EM analysis revealed, while AGD filaments, which have a four-layered fold, are similar to those from CBD;
  • filaments with the AGD fold are also found in intron 10 mutation cases; and
  • the structures of tau filaments from cases of FBD and FDD are the same as those from Alzheimer’s disease and PART.

But what do we know about the molecular mechanisms by which the different folds are formed?

“Not much,” says Sjors. “As we have now solved the structures from most tauopathies, the focus of our research will now change to exactly this question: which factors are important for the different folds to form, and how do these factors relate to each of the different diseases.

Benjamin Falcon researches the structures of tau proteins at the MRC LMB. Picture: Keith Heppell
Benjamin Falcon researches the structures of tau proteins at the MRC LMB. Picture: Keith Heppell

“To do this, we will use different model systems to try and replicate the disease-related folds in the lab, for example by making tau filaments in the test tube or in human cell lines.”

Deciphering these critical molecular mechanisms would represent a major breakthrough with huge implications for the diagnosis and treatment of tauopathies.

Read more

Sjors Scheres, of MRC LMB, earns Royal Society Leeuwenhoek Medal for innovations in cryo-EM image analysis

MRC LMB’s Michel Goedert receives Royal Society's 2019 Royal Medal for his neurodegenerative disease work

Rising star Dr Ben Falcon at MRC LMB explores role of tau in dementia

Dr Jan Löwe on the next frontier for MRC Laboratory of Molecular Biology in Cambridge

Winner of Brain Prize 2018, Michel Goedert, on our best hope for tackling Alzheimer's disease

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