The structure of tau protein filaments in Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia, is reported this week in Nature.
Many neurodegenerative diseases feature the accumulation of tau proteins, which assemble to form filaments in the brain. Tau proteins may contain three or four microtubule-binding repeats (3R or 4R), and filaments may contain 3R tau, 4R tau, or a mix of both. Michel Goedert, Sjors Scheres, and colleagues used cryo-electron microscopy (cryo-EM) to determine the structures of tau filaments extracted from the frontotemporal cortex of a patient with Pick’s disease. The authors, who previously reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau, found that the ordered cores of tau filaments from the Pick’s disease patient adopted a single, novel fold of 3R tau, distinct from the tau filament fold found in Alzheimer’s disease.
The identification of disease-specific folds in tau filaments provides evidence for the hypothesis that different conformations of filamentous tau give rise to distinct clinical phenotypes. Unpicking these different folds and shapes will lead to better understanding of a wide range of diseases related to abnormal protein aggregation.
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