Massively parallel screening of small molecules modifiers of amyloid nucleation in Alzheimer’s Disease

Area of Knowledge: LIFE SCIENCES

Group Leaders

Benedetta Bolognesi, Institute for Bioengineering of Catalonia (IBEC) ·


Alzheimer’s disease, the leading cause of dementia, affects 55 million people world-wide. Unfortunately, the search of therapies able to prevent or treat Alzheimer’s disease has faced 30 years of failed clinical trials. Familial forms of AD are caused by mutations in the amyloid-beta peptide speed up the aggregation of the peptide into amyloid fibrils. One of the challenges in developing molecules able to prevent amyloid-beta aggregation is that the process of amyloid nucleation is extremely difficult to characterise in vitro. It is even more difficult to envision methods that can do this at scale, i.e. approaches able to scan many molecules and to parallel asses their activity on all genetic variants of amyloid beta. We have developed a massively parallel reporter of amyloid nucleation which provides an excellent and cost-effective platform to screen for molecules and mechanisms able to prevent amyloid nucleation in vivo (Seuma et al 2021, Seuma et al 2022). This translational project will make use of this approach and involve three phases: 1) optimisation of our high-throughput in-vivo system for the uptake of small molecules; 2) screening of chemical libraries for their impact on amyloid nucleation (to be performed at the IRB drug screening facility) ; 3) validation of the top hits against different genetic variants of amyloid beta to lay the bases for personalised treatment in AD. As a result, we will be able to identify small molecules able to tamper the crucial biophysical mechanism that is leading to AD, while providing a platform that can then be used to screen for modifiers of amyloid nucleation for other proteins that aggregate into amyloids in human disease. 

Job position description

Our lab has a wide set of expertise ranging from genetics and molecular biology to biophysics and bioinformatic. As a student in our lab, you will get exposed to all these disciplines. Most of the projects in the lab involve deep mutational scanning, but lab members are able to choose the appropriate system and approach for their specific question and for each stage of their project. This creates a highly inter-disciplinary environment, with many members of the lab using both computational and experimental approaches.  Therefore, a strong interest in developing both experimental and computational skills is required. PhD students in the lab have so far had very successful trajectories with first author publications, as well as selected talks and prizes at international conferences. For perspective candidates wanting to join the lab, experience with genomics, yeast genetics and bioinformatics will be beneficial. More specifically, in this project, you will also learn how to logistically organize a high-throughput screening platform. Our PhD students are encouraged and supported to “think big”, be ambitious and independent.