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

Badia, M., Bolognesi, B., (2021). Assembling the right type of switch: Protein condensation to signal cell death Current Opinion in Cell Biology 69, 55-61

Protein phase transitions are particularly amenable for cell signalling as these highly cooperative processes allow cells to make binary decisions in response to relatively small intracellular changes. The different processes of condensate formation and the distinct material properties of the resulting condensates provide a dictionary to modulate a range of decisions on cell fate. We argue that, on the one hand, the reversibility of liquid demixing offers a chance to arrest cell growth under specific circumstances. On the other hand, the transition to amyloids is better suited for terminal decisions such as those leading to apoptosis and necrosis. Here, we review recent examples of both scenarios, highlighting how mutations in signalling proteins affect the formation of biomolecular condensates with drastic effects on cell survival.

Keywords: Amyloid, Cell death, Deep mutagenesis, LLPS, RNA-binding proteins


Seuma, M., Faure, A., Badia, M., Lehner, B., Bolognesi, B., (2021). The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer’s disease mutations eLife 10, e63364

Plaques of the amyloid beta (Aß) peptide are a pathological hallmark of Alzheimer’s disease (AD), the most common form of dementia. Mutations in Aß also cause familial forms of AD (fAD). Here, we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aß. The resulting genetic landscape reveals mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the empirical nucleation scores accurately identify all known dominant fAD mutations in Aß, genetically validating that the mechanism of nucleation in a cell-based assay is likely to be very similar to the mechanism that causes the human disease. These results provide the first comprehensive atlas of how mutations alter the formation of any amyloid fibril and a resource for the interpretation of genetic variation in Aß.


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