About
Our lab aims at understanding how genetic changes between individuals can or cannot result in disease by quantifying the impact mutations have on protein aggregation and toxicity.
We are particularly interested in amino acid sequences that can adopt different conformations and undergo a process of self-assembly which results in distinct physical states.
Protein self-assembly
The aggregation of proteins into insoluble amyloid fibrils is a key process in the pathogenesis of a number of neurodegenerative conditions, such as Parkinson’s disease or Amyotrophic Lateral Sclerosis. However, examples of functional amyloid are also widespread in nature, especially across bacteria and fungi. Our work aims at systematically deciphering the sequence-dependencies of the process of aggregation in both functional and pathological contexts.
Proteins can also self-assemble into a more dynamic and reversible state through a process of condensation which is thought to contribute to the organization of the intracellular space. However, also for proteins that undergo liquid-demixing to form biomolecular condensates, the balance between function and dysfunction is far from clear. It is also unknown if and how condensates are precursors of insoluble amyloid-like states, and to which extent proteins are structured once in the liquid state.
Quantifying the impact of mutations at scale
In order to understand how mutations affect these delicate equilibria and to elucidate when and why a sequence starts aggregating or becomes toxic for the cell, our lab integrates experimental and computational approaches in different model systems. Recently, we have developed different Multiplexed Assays of Variant Effects (MAVEs) to quantify the toxicity and aggregation propensity of hundreds of thousands of protein sequences in vivo. By capturing the full landscape of the effects of mutations in a specific protein sequence we can guide clinicians to better diagnose and treat human disease, but we also reach a comprehensive mechanistic understanding of the process of amyloid formation and protein-induced toxicity. This translates in the possibility of rationally developing better targeted therapeutics, as well as in a set of fundamental principles that can guide protein design in bioengineering.
Developing novel strategies to report on protein conformation
In collaboration with the Lehner lab we also develop combinatorial mutagenesis approaches to study the interactions between mutations. We then use such genetic interactions to report on the conformation different proteins adopt as they start aggregating. Overall, we aim at generating exhaustive datasets that will give mechanistic insights on the process of protein aggregation, while also reporting on specific conformations and mechanisms leading to cellular toxicity. The massive amount of data we generate is used to train new models of protein aggregation. Our strategy is also amenable to tackle many intrinsically disordered proteins, which are particularly difficult to study in vitro. In this perspective, in vivo selection approaches such as the ones we develop can provide a unique opportunity to investigate these sequences in a systematic way.
Map of the effect of mutations on toxicity of the TDP-43 Prion-like Domain.
Percentage of substitutions and insertions increasing or decreasing amyloid formation of the Amyloid-Beta peptide, visualized on the cross-section of ex-vivo fibrils (7Q4M).
Staff
ibecbarcelona.euProjects
| NATIONAL GRANTS | FINANCER | PI |
|---|---|---|
| AMYNDEL · Deciphering the consequences of different types of genetic variation in amyloid forming sequences by deep mutagenesis ( 2022-2025) | MICIU · Generación Conocimiento: Proyectos I+D | Benedetta Bolognesi |
| DeepAmyloids · Massively parallel mutagenesis to understand, predict and prevent amyloid nucleation in neurodegenerative diseases (2021-2024) | Obra Social La Caixa | Benedetta Bolognesi |
| FINISHED PROJECTS | FINANCER | PI |
|---|---|---|
| Poly-STOP · Developing modulators of protein aggregation in polyglutamine diseases by deep mutational scanning (2021-2022) | BIST · Barcelona Institute of Science and Technology | Benedetta Bolognesi |
| PRIOMUT · Escaneado exhaustivo de mutaciones en un dominio priónico para entender la toxicidad inducida por proteínas (2019-2021) | MICIU / Retos investigación: Proyectos I+D | Benedetta Bolognesi |
Publications
Equipment
- Thermo MaxQ 8000
Collaborations
- Priyanka Narayan
NIH-NIDDK - Xavier Salvatella
IRB, Barcelona - Fran Supek
IRB, Barcelona - Ben Lehner
CRG, Barcelona - Luke McAlary /Justin Yerbury
University of Wollongong, Australia
News
IBEC researchers win two “BIST Ignite Seed Grants”
IBEC researchers receive two “Ignite Seed Grants” to combine their skills with other BIST members to seek scientific answers to health challenges. Benedetta Bolognesi will study, with the IRB, Huntington’s disease and other neurodegenerative pathologies without treatment. On the other hand, Juan Manuel Fernández-Costa and researchers at ICFO will develop muscles-on-a-chip and biomagnetism sensors to accelerate the design of new treatments for muscular dystrophy.
One more step towards early detection of Alzheimer’s
Benedetta Bolognesi, junior group leader at IBEC, appears in different media for a recent study published in the eLife magazine. In the study they show the first map with all the possible mutations in the amyloid beta peptide and tested how they influence its aggregation into plaques, a pathological hallmark of Alzheimer’s disease.
First comprehensive map of amyloid plaque mutations opens new avenues for early detection of Alzheimer’s disease
A study published in the journal eLife made all the possible mutations in the amyloid beta peptide and tested how they influence its aggregation into plaques, a pathological hallmark of Alzheimer’s disease.
Benedetta Bolognesi featured at “Maldita Ciencia” talking about coronavirus
Benedetta Bolognesi, group leader at IBEC has been collaborating with “Maldita Ciencia” to clarify doubts and rumours about Covid-19″.
IBEC receives a visit from the Mayor of Barcelona interested in our research against Covid19
The Mayor of Barcelona, Ada Colau, visited IBEC facilities last Friday to learn, by our Director and a group of researchers, how bioengineering can help find solutions to health problems such as COVID19, cancer, or degenerative diseases. When in early 2020, more than 200 scientists gathered in La Pedrera in Barcelona to discuss the present and future of bioengineering, no one imagined that the world would experience the first pandemic of the 21st century and that science would take on more importance than ever.
Researchers perform thousands of mutations to understand amyotrophic lateral sclerosis
Researchers from IBEC and CRG in Barcelona use a technique called high-throughput mutagenesis to study Amyotrophic Lateral Sclerosis (ALS), with unexpected results. Results showed that aggregation of TDP-43 is not harmful but actually protects cells, changing our understanding of ALS and opening the door to radically new therapeutic approaches. Amyotrophic lateral sclerosis (ALS) is a devastating and incurable nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control and normally death within a few years of diagnosis. In ALS, like in other neurodegenerative diseases, specific protein aggregates have long been recognized as the pathological hallmarks, but it is not clear whether they represent the actual cause of the disease. Indeed, alleviating aggregation has repeatedly failed as a therapeutic strategy when trying to treat neurodegenerative diseases such as Alzheimer’s disease.
New IBEC group creates ‘fitness heatmaps’ of gene mutations
The start of the autumn semester finds a new face in IBEC’s research community, with Dr. Benedetta Bolognesi joining the institute as junior group leader. Benedetta has come from Barcelona’s Centre for Genomic Regulation, where she was a postdoc in Ben Lehner’s and Gian Gaetano Tartaglia’s groups. At IBEC she will launch and lead the Protein Phase Transitions in Health and Disease group. During her postdoc, Benedetta focused on why certain genes are toxic when over-expressed. She found that, in some cases, they cause toxicity because the proteins they code for end up forming a different liquid phase in the cytoplasm.
Jobs
Lab Technician at the Protein phase transitions in health and disease Research Group
Ref: Lab Technician / Deadline: 29th July 2022
2 Postdoctoral researchers at the Protein Phase Transitions in Health and Disease Research Group
Application Deadline: 24/10/2021Ref: PD-BB The Protein phase Transitions in Health and Disease group at the Institute for Bioengineering of Catalonia (IBEC) is looking for two Postdoctoral Researchers to develop deep mutagenesis projects in the context of amyloid forming proteins. The contract will be within the framework of a larger project funded by La Caixa.