Many neurodegenerative diseases, including Alzheimer’s disease and Pick’s disease, are associated with the ordered assembly of tau protein into abnormal filaments, the abundance of which is strongly correlated with disease symptoms. Tau filaments are found to have disease-specific distributions within the nervous system, as well as distinct biochemical properties. This led to the hypothesis that tau filaments might fold into disease-specific structures.
In this paper published in Nature is explained how, to investigate this, the LMB team extracted tau filaments from the brain of a patient with Pick’s disease and collected images of the filaments using Cryo-EM. The team were then able to construct a 3D model of the tau filaments using these images and determine the molecular structure of the tau protein within these filaments.
Previously, they had solved the structures of tau filaments from patients with Alzheimer’s disease. Comparison of the new structures of filaments from patients with Pick’s disease with those from Alzheimer’s disease demonstrated that the structures are indeed different. These differences may be responsible for the distinct patterns of accumulation in the brain seen between the two variants and for the different ways in which these diseases affect patients.
Schematic representation of the secondary structure elements in the Pick and Alzheimer folds, depicted as a single rung. The positions of C322 and D348, which differ between the two folds, are highlighted. The symbols mark conserved turns of homologous regions in the two folds.
This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking (www.imi.europa.eu) under grant agreement No 116060. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.
The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.