Staff member


Benedetta Bolognesi

Junior Group Leader
Protein phase transitions in health and disease
bbolognesi@ibecbarcelona.eu
+34 934 035094 (Lab)
CV Summary

Benedetta Bolognesi was a graduate student in the Department of Chemistry at the University of Cambridge (UK) under the supervision of Prof. Chris Dobson. There, her work focused on the intrinsic determinants of aggregation and toxicity of the amyloid-beta peptide. Then, she moved to the Centre for Genomic Regulation (Barcelona, Spain) with an interdisciplinary Marie Curie fellowship to elucidate the mechanisms underlying dosage sensitivity in yeast. Towards the end of her post-doc she developed a deep mutational scanning (DMS) strategy to quantify the effect of thousands of mutations in disordered protein domains. That is what got her into DMS - an approach she and her team use now in the lab to answer a wide range of biological questions, with a particular focus on proteins that form liquid condensates and amyloids.

Staff member publications

Bolognesi, Benedetta, Faure, Andre J., Seuma, Mireia, Schmiedel, Jörrn M., Tartaglia, Gian Gaetano, Lehner, Ben, (2019). The mutational landscape of a prion-like domain Nature Communications 10, (1), 4162

Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.

Keywords: Computational biology and bioinformatics, Genomics, Mechanisms of disease, Neurodegeneration, Systems biology


Bolognesi, Benedetta, Lehner, Ben, (2018). Reaching the limit eLife 7, e39804

How many copies of a protein can be made before it becomes toxic to the cell?

Keywords: Protein burden, Overexpression, Glycolysis