The Mutational Landscape of Proteins containing Prion Domains

Group: Protein phase transitions in health and disease
Group leader: Benedetta Bolognesi (bbolognesi@ibecbarcelona.eu)

Proteins implicated in neurodegenerative diseases are able to populate multiple physical states in the cytoplasm: diffuse, liquid de-mixed, solid aggregate. Pathological mutations affect these equilibria in ways we cannot yet understand or predict. This project will focus on proteins implicated in Amyotrophic Lateral Sclerosis (ALS). The first phase of this project will consist of a quantitative description of how mutations can affect the formation of liquid-like or solid aggregates and how such different states can trigger cell toxicity. We will use deep mutagenesis1 in human cell lines as a model to measure both aggregation and toxicity of thousands of protein variants at the same time. On the basis of this  approach that combines biophysics to genomics we will decipher the molecular mechanism underlying ALS and validate them in more complex models.

Bolognesi, B. et al. The mutational landscape of a prion-like domain. Commun. 10, 4162 (2019).