The pathological transformation of tau protein is one of the molecular hallmarks of neurodegenerative diseases such as Alzheimer’s disease and tauopathies, where tau is found hyperphosphorylated and aggregated. The abnormal tau protein is released into the extracellular environment and can spread from one neuron to another, transmitting the pathological misfolded conformation to other normal tau molecules by a prion-like mechanism; this process is called “seeding”. The early molecular modification of tau that trigger its pathological transformation are poorly understood, and detection of the seeding activity is the subject of intense research. Elucidating the cellular environment conditions that promote tau pathological transformation, as well as the detection of seeding activity, are thus of therapeutic importance in preventing or slowing down the development of tau-related diseases.
The team of Ralf Jockers with Erika Cecon and Julie Dam, in collaboration with the pharmaceutical company Servier (France) developed new biosensors based on the highly sensitive nanoluciferase enzyme complementation (NanoBiT) technique, to monitor conformational modifications and aggregation of tau protein in living cells (see figure).
In this study they show that the new biosensors are able to monitor:
i. molecular proximity of physiological normal tau at microtubules;
ii. changes in tau conformation and self-interaction associated with tau phosphorylation,
iii. the seeding activity induced by mouse brain lysates of a mouse model of tau pathology.
Importantly, they provide proof of concept with suitability of the assay to identify or validate compounds interfering with the pathological tau transformation, as the assay is high-throughput-compatible and provide a quantitative read-out.
This novel repertoire of tau biosensors opens new perspectives for the disclosure of molecular mechanisms underlying pathological tau transformation in living cells, and to discover new drug candidates for tau-related neurodegenerative diseases.
This work was funded by the Inserm, the CNRS and Servier Laboratories, and supported by the fondation Philippe Chatrier.
Cecon E, Oishi A, Luka M, Ndiaye-Lobry D, François A, Lescuyer M, Panayi F, Dam J, Machado P, Jockers R. Elife. 2023 Mar 14;12:e78360. doi: 10.7554/eLife.78360.