Corticobasal Degeneration Reveals Its Signature by Tau Strains

Corticobasal degeneration (CBD) and progressive supranulcear palsy are neurodegenerative diseases characterized by motor and cognitive disturbances and categorized as 4R-tauopathy according with the current molecular classification of frontotemporal lobar degeneration (FTLD-tau). Such a definition refers to the abundant filamentous tau inclusions made of isoforms with 4 microtubule-binding repeats (4R) found in both diseases. Conversely, in Pick’s disease, filaments are made of 3 repeat (3R) tau isoforms, whereas in Alzheimer’s disease and in chronic traumatic encephalopathy both 3R and 4R tau isoforms are folded in the filaments. Although several dissimilarities exist, pathologic as well as clinical commonalities justify combining CBD and progressive supranulcear palsy together within the context of clinical trials testing anti-tau monoclonal antibodies as disease-modifying therapy. Yet, preliminary evidence suggests that tau prion propagation in mammalian cell lines requires isoform pairing between the infecting prion and the recipient substrate, supporting the fact that successful anti-tau therapeutic strategies will require inhibiting the propagation of specific and selected strains of the pathologic tau protein. The adult human brain expresses 6 tau isoforms ranging from 352 to 441 amino acids produced by alternative mRNA splicing. Tau isoforms differ for the presence or absence of inserts of 29 or 58 amino acids in the amino-terminal half as well as for the inclusion or not of the 31 amino acid microtubule-binding repeat in the carboxy-terminal half. In CBD, tau isoforms have the latter repeated 4 times (4R). The 4 repeats (R1–R4) comprise residues 244 to 368 in the numbering of the 441 amino acids. Zhang and colleagues investigated for the first time the structure of tau filaments extracted from the frontal cortex of 3 patients with CBD using electron cryo-microscopy. The core of CBD filaments includes residues K274-E380 of tau spanning the last residue of R1; the whole of R2, R3, and R4; and 12 amino acids after R4. The structure is constituted by a 4-layered fold that encloses a large nonproteinaceous density. The tau filament structure was identical between CBD patients, but distinct from those with Alzheimer’s disease, Pick’s disease, and chronic traumatic encephalopathy. CBD is the first 4R tauopathy with a known filament structure. In other 4R tauopathies, such as progressive supranulcear palsy, the structures of tau filaments remain to be determined. Although evidence suggests that tau inclusions form first in the astrocytes of the striatum and frontal cortex and then spread to other regions, because the authors analyzed samples only from the frontal cortex, we cannot exclude tau filament structure is different according to brain localization. This study proved that differences in filament structures are observed between diseases, but not between subjects with a given disease, consistent with the existence of distinct conformers of assembled tau in different tauopathies. Although such results are noteworthy, they require external validation in larger samples of postmortem findings considering strategies to limit the impact of cohort effects. The structural analysis of tau isoforms may provide insights into what drives the specificity of tau conformers and in turn lead to novel therapeutic opportunities tailored on distinct disease entities. Developing interdisciplinary research teams including clinicians, pharmacologists, structural biologists, neuropathologists, and translational neuroscientists will be pivotal for identifying disease-modifying treatments in neurodegenerative disorders. Furthermore, defining the structure of tau filaments in progressive supranulcear palsy will shed further light on the usefulness to classify progressive supranulcear palsy and CBD as different disorders.