Missions

Aggregates of the alpha-Synuclein protein are related to different neurodegenerative diseases. However, the mechanisms of its aggregation are not fully understood, and recent evidence for prion-like propagation of alpha-Synuclein fibrils led to a new vision of the associated pathologies. One technique to study (and potentially diagnose) synucleinopathies, notably at their early stages, is real-time quaking-induced conversion (RT-QuIC). RT-QuIC is an amplification technique that builds on the prion-like character of alpha-Synuclein fibrils to induce a “chain aggregation reaction” from minute amounts of pathogenic material, e.g. clinical samples. If the clinical seed is indeed pathogenic, the apparition of fibrils is detected within hours through fluorescence measurements, based on the specificity of fluorophores, like thioflavin T (ThT). The robustness of the RT-QuIC assays is nevertheless still limited in the case of synucleinopathies. Indeed, the sensitivity of ThT to different fibril morphologies, and possibly different structural strains of alpha-Synuclein is still debated.
YOUR JOB as a research associate within the MS-QuIC project will consist in following the evolution of RT-QuIC media seeded with different samples from the clinical collection available at CRNL. The complementarity of charge detection mass spectrometry (CDMS) and ion mobility/mass spectrometry (IMS-MS), will allow to gain unique insight in the aggregation process across an unprecedented size range from the early oligomers to the mature fibrils. These measurements will be correlated with online fluorescence detection based on a modified nanoelectrospray source developed in house.

Activities

- Use of unconventional experimental devices developed in the laboratory (charge-detection mass spectrometry, tandem ion mobility spectrometry, modified nanoelectrospray ionization source), optimization of experimental methods
- Development of a suitable sample preparation strategy in collaboration with a team of clinical biologists
- Data processing and rationalization in collaboration with a team of clinical biologists

Skills

PhD holder, enthusiastic, with an experience in mass spectrometry/ion mobility spectrometry for the structural characterization of biomolecules, and sample preparation for native MS. Python programming skills and knowledge in spectroscopic methods would be a plus!

Work Context

The host team is the iLM's spectrobio team, which comprises approximately 25 people (including around fifteen doctoral students and fixed-term researchers) conducting research in the fields of mass spectrometry and optical spectroscopy.
The recruitment will take place within the framework of the interdisciplinary ANR MS-QuIC project, the result of a collaboration between the spectrobio team and a team of clinical biologists from the Lyon Center for Neuroscience Research (CRNL), specializing in the development of the RT-QuIC method for the study and detection of neurodegenerative diseases.
The recruited person will work under the supervision of F. Chirot and R. Antoine, at the interface between the two teams involved (clinicians and physicists/chemists), and will collaborate closely with an engineer recruited as part of the project as well as a doctoral student.

Constraints and risks

Handling of biological material