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Research Groups

Simon Alberti

Organization of cytoplasm across space and time

Previous and Current Research

Many key biochemical reactions take place in the cytoplasmic environment. However, we still know very little about the organization of the cytoplasm and the role of specialized cytoplasmic compartments such as RNP granules in regulating cellular functions. My research group aims to elucidate molecular principles underlying the spatiotemporal organization of the cytoplasm. We are particularly interested in understanding how the cytoplasm changes upon environmental perturbations and stress (Figure 1). Stressed cells undergo controlled changes on many levels to alter their physiology and metabolism. Many of these changes may directly result from alterations in the structure and organization of the cytoplasm. Understanding these structural changes and how they promote organismal survival is our key aim.

To investigate this question, we use cell biological, biochemical, biophysical and genetic approaches and diverse model systems, such as yeast, Dictyostelium, and cultured mammalian cells, thus allowing us to cover a wide range of different organismal life styles. Our findings so far indicate that the mechanisms by which macromolecules assemble into compartments are diverse and involve dedicated cellular factors, such as prion-like proteins that promote the formation of liquid compartments, or protein self-assembly pathways that are controlled by changes in global parameters such as the cytosolic pH.

Importantly, the ability to form such compartments comes with a cost, as many compartment-forming proteins have a high propensity to misfold and aggregate. Indeed, we could recently show that compartment-forming proteins have very unusual molecular properties and are associated with age-related diseases (Patel et al., 2015). Thus, our long-term aim is to gain insight into the important link between the compartment-forming abilities of proteins and age-related protein misfolding diseases.

Simon Alberti research: figure — Figure 1: Research focus of the Alberti lab. The figure shows an idealized cell, which transitions into a different state upon stress. This transition is associated with changes in the organization of the cytoplasm and the formation of large macromolecular assemblies. In normal cells, the macromolecules are not interacting with each other (unassembled). However, upon stress, these macromolecules interact and form assemblies with specific material properties (liquid or solid condensed matter state). Thus, the overall process has hallmarks of a phase transition. Stress-induced assemblies can either function as storage depots or as compartments for concentrated biochemical reactions.

Future Projects and Goals

Identify protein factors, domains, and sequence motifs that are required for the formation of macromolecular assemblies
Analyze the molecular mechanisms underlying the formation of macromolecular assemblies, with a focus on the protein quality control machinery, post-translational modifications, and the cytoskeleton
Proteome-wide genetic and chemical screens to identify modifiers of macromolecular assembly
Investigate how the ability to form macromolecular assemblies affects the physiological state of a cell, determines developmental decisions, and contributes to diseases and aging

Methodological and Technical Expertise

Genetics and cell biology of S. cerevisiae, Dictyostelium, and cultured mammalian cells
Fluorescence microscopy and time-lapse imaging
Biophysical approaches such FRAP and photoconversion to study intracellular dynamics
Biochemical reconstitution assays and in vitro and in vivo aggregation assays

Selected Publications

Avinash Patel, Hyun-Ok Kate Lee, Louise Jawerth, Shovamayee Maharana, Marcus Jahnel, Marco Y Hein, Stoyno Stoynov, J. Mahamid, Shambaditya Saha, Titus Franzmann, Andrei Pozniakovski, Ina Poser, Nicola Maghelli, Loic Royer, Martin Weigert, Eugene W Myers, Stephan W. Grill, David N. Drechsel, Anthony Hyman, Simon Alberti
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.
Cell, 162, pp. 1066–1077. (2015)

Sonja Kroschwald, Shovamayee Maharana, Daniel Mateju, Liliana Malinovska, Elisabeth Nüske, Ina Poser, Doris Richter, Simon Alberti
Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules.
Elife, 4, e06807. (2015)

Liliana Malinovska, Sandra Palm, Kimberley Gibson, Jean-Marc Verbavatz, Simon Alberti
Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation.
Proc Natl Acad Sci USA, 112, pp. 2620–2629 (2015)

Ivana Petrovska, Elisabeth Nüske, Matthias Munder, Gayathrie Kulasegaran, Liliana Malinovska, Sonja Kroschwald, Doris Richter, Karim Fahmy, Kimberley Gibson, Jean-Marc Verbavatz, Simon Alberti
Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation.
Elife, 3, e02409. (2014)

Alberti S, Halfmann R, King O, Kapila A, Lindquist S
A systematic survey identifies prions and illuminates sequence features of prionogenic proteins.
Cell, 137, pp. 146–158. (2009)

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