Job ID: 106646

PhD Project – Tau droplets inhibitors: a new class of anti-neurodegenerative disease compounds

Position: Ph.D. Student

Deadline: 2 April 2023

Employment Start Date: 2 October 2023

Contract Length: 3 years

City: Marseille

Country: France

Institution: Aix Marseille Université

Department: Institute of NeuroPhysiopathology (INP)


The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD scholarships for students with a master’s degree in a non-French university.

The following project is one of the 14 proposed projects. Not all proposed projects will be funded, check our website for details.

State of the art – Reduced microtubule stability, which plays an important role in axonal transport has been observed in several neurodegenerative diseases (ND) such as Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. It is often associated with dissociation of tau protein, which stabilizes microtubules. Under pathological conditions tau is hyperphosphorylated and aggregates in the form of paired helical filaments, the main component of neurofibrillary tangles found in many NDs. Thus, one of the main strategies of fighting these currently uncurable diseases consists in finding efficient inhibitors of tau aggregation. Recently it was demonstrated that formation of droplets during liquid-liquid phase separation (LLPS) of tau could be the first step that trigger tau aggregation. In our lab, we have developed a new high throughput assay that allow to follow LLPS formation using nanoDSF instrument.

Objectives – Thus, the objective of the proposed PhD project is to identify anti-neurodegenerative disease compounds by targeting inhibition of tau LLPS using our newly developed screening assay.

Methods – This will be achieved through several steps using in vitro, in cells and ultimately in vivoapproaches that PhD student will learn and apply at Institute of neurophysiopathology. First, we will screen a protein-protein interaction inhibitors library to identify potential candidates. Second, found inhibitors will be investigated in detail to rank them for their ability to inhibit both LLPS and paired helical filaments formation. Their interaction with tau will be characterized using biophysical methods such as isothermal titration calorimetry, analytical ultracentrifugation, surface plasmon resonance and mass spectrometry to understand the molecular mechanism of inhibition. Third, the ability of the compounds to inhibit tau LLPS will be investigated using neuronal cell models. For that purpose, intracellular droplets formation and the impact of inhibitors on this process will be followed using fluorescence microscopy and cell that overexpress tau-EGFP. Finally, compounds that exhibit strong propensity to inhibit LLPS formation in cells will be tested on mice models of tauopathies.

Expected results – By the end of PhD project we expect to identify several scaffolds able to inhibit LLPS of tau in cells and obtain preliminary results of its efficiency on mice models.

Feasibility – Institute of neurophysiopathology possesses all necessary infrastructure, facilities, and expertise for successful accomplishment of the project. All in vitro experiments including screening will be performed at platform PINT of INP which has all necessary instrument and already performed nanoDSF screenings. In cell experiments will be performed on the facilities of team 9 “Cytoskeleton and Neurophysiopathology” that has an experience to follow tau aggregation in cellular models. Finally, in vitro experiments will be carried out at animal facilities of INP which also has a solid background in experimentation on mice models of neurodegenerative diseases.

Expected candidate profile – We expect to find highly dynamic and motivated candidate for this project, who willing to acquire a broad range of methods from in vitro biophysical and cellular methods to in vivo methods. Strong background in molecular and cell biology is required.