Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated blows to the head, particularly in relation to contact sports, such as American football and boxing. Understanding of the disease is limited and there is no available treatment. Definitive diagnosis currently depends on examination of the brain after death. Work by Michel Goedert’s group in the LMB’s Neurobiology Division and Sjors Scheres’ group in the LMB’s Structural Studies Division, in collaboration with Bernardino Ghetti and colleagues at Indiana University, and Kathy Newell at the University of Kansas, has revealed the high-resolution structures of the abnormal tau assemblies associated with CTE, which could lead to improved diagnosis and treatment.
Groups at risk of developing CTE include military veterans, victims of assault, and people with poorly controlled epilepsy that results in repeated head trauma, as well as American football players, boxers, and rugby players. However, the exact causes are not fully understood and it is not known why only a subset of individuals exposed to repetitive head impacts appear to develop CTE. Symptoms of CTE include behavioural and mood changes, increased confusion, and memory problems, all of which may begin to develop several years after the head impacts and often get worse over time.
CTE, like Alzheimer’s and Pick’s diseases, is associated with the formation of filamentous assemblies of tau protein. Previously, Michel’s and Sjors’ groups solved the structures of tau filaments from patients with Alzheimer’s disease and from patients with Pick’s disease, and demonstrated that these assemblies have different folds. This might explain the distinct patterns of accumulation of tau protein in each disease. In the new study, Benjamin Falcon, from Michel’s group, extracted tau filaments from the brains of three individuals with clinically and neuropathologically confirmed CTE – one former professional American football player and two former professional boxers. Benjamin imaged these samples, using the electron cryo-microscopy facilities at MRC-LMB, Diamond Light Source and Leicester University, to determine the structures of tau assemblies in CTE.
Although identical tau structures were seen in the CTE patients, they were different from those seen in Alzheimer’s and Pick’s diseases. One striking difference between the CTE fold and the Alzheimer fold is the presence of a cavity in the CTE fold, which is filled with other molecules. The chemical nature of these molecules has not yet been identified, but it is thought that they may play a role in the assembly of tau into filaments and that their abundance may determine why some individuals develop CTE, while others do not.
Tau molecules found in the abnormal filaments of Pick’s disease are biochemically and structurally different from those of Alzheimer’s disease. In contrast, tau protein of CTE filaments folds into different structures, but is thought to be biochemically identical to that in the filaments of Alzheimer’s disease. Therefore, the new work provides support for the view that filament structures define tau-associated neurodegenerative diseases.
The fact that the structures of tau filaments were identical in all three individuals suggests that this could be a unifying neuropathological criterion for the diagnosis of CTE. Knowledge of these structures may make it possible to design tracer compounds that will bind specifically to the tau fold of CTE which may be used to diagnose CTE in living patients. Understanding how and why tau assembles into disease-specific folds will also be beneficial for the development of new therapies.
This work was funded by the MRC, the European Union, the US National Institutes of Health, the Department of Pathology and Laboratory Medicine at Indiana University School of Medicine and the Department of Pathology and Laboratory Medicine at University of Kansas School of Medicine.
Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Falcon, B., Zivanov, J., Zhang, W., Murzin, AG., Garringer, HJ., Vidal, R., Crowther, RA., Newell, KL., Ghetti, B., Goedert, M., Scheres, SHW. Nature 568: 420-423
Michel Goedert’s group page
Sjors Scheres’ group page
Indiana University Department of Pathology and Laboratory Medicine’s page
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