Genetically identical cells frequently assume different fates and phenotypes. This diversity is widespread in nature and plays a fundamental role in processes ranging from adaptation to development to disease. We employ evolutionary divergent models to identify functionally conserved mechanisms that enable cells to differentiate their processes. We also aim to decipher how these dynamic re-organization events are spatially coordinated within cells.
Our research focuses on an emerging area of proteostasis: how protein folding and assembly-switches modulate cellular information flow. We apply multidisciplinary approaches, including proteomic screens, biochemical reconstitutions, genome editing, live-cell imaging, and microfluidics to investigate how changes in particular protein folding/assembly states translate into cellular decision making and individuality.
Aging is accompanied by a variety of molecular changes. These changes increase phenotypic heterogeneity among cells, which can have detrimental consequences. Indeed, aging is the main risk factor for a large number of maladies, including (neuro)degenerative diseases, cardiovascular diseases and cancer.
We are interested in elucidating how changes in the protein folding landscape contribute to phenotypic heterogeneity during aging, how these changes contribute to the aging process itself, and how aged cells can give rise to rejuvenated progeny. We employ the budding yeast (Saccharomyces cerevisiae) model, which has a finite replicative life span of approximately 25 division cycles. Remarkably, through asymmetric cell division, the aged cells give rise to daughter cells with a restored lifespan potential. Thus, this organism provides a powerful system to study the consequences of aging at the molecular level, their phenotypic effect, and how such age-related changes are spatially regulated.
Proteins are responsible for almost all cellular phenotypes. To carry out their proper function, proteins need to fold into a particular structure. This is facilitated by factors, such as chaperones, that maintain protein quality control. Failures in proteostasis can lead to protein misfolding and aggregation – phenomena frequently associated with aging and age-related diseases. Intriguingly, a number of proteins have an intrinsic propensity to alternate between different conformational states and to transition between soluble and assembled states. However, little is known about how these dynamic transitions are shielded form misfolding and how they contribute to the phenotypic landscape of cells and organisms.
In collaboration with the Picotti lab (ETH Zurich), we have recently surveyed the yeast proteome to identify proteins that undergo structural rearrangements in response to aging. Using this dataset as our roadmap, we are currently elucidating how aging leads to structural rearrangements in proteins regulating translation, metabolism, and proteostasis, and how these changes contribute to known and novel aging phenotypes. We are also interested elucidating how cells are able to coordinate the retention of such phenotypes during cell division in order to give rise to rejuvenated progeny.
Proteostasis has a profound effect on how genotypes are translated into phenotypes. However, little is known about its role in major evolutionary transitions. We employ a multicellular budding yeast model that has been experimentally evolved in Will Ratcliff’s laboratory by selecting for larger size. Over thousands of generations of selection, this experiment has resulted in multicellular groups that are over 20,000 times larger and 10,000 times more mechanically robust than their ancestors. Using this model, we investigate the role of proteostatic tuning in the emergence of multicellular adaptations and explore whether cellular aging plays a role in the origin of spatial developmental patterns.
Brains encompass an astonishing ability to store information of transient experiences. Hence, no two brains are wired exactly the same. The ability to store information is rooted in neuronal circuits that rely on unique morphological and functional features of single neurons. During learning, new synaptic contact points are formed between adjacent neurons. These synapses need to be strengthened and stabilized over long periods of time in order to form a memory the acquired information. The second thrust of our research program aims at understanding how the post-synaptic compartments (dendritic spines) establish and maintain individualized biochemistries during synaptic strengthening. For this, we combine systems biology and advanced imaging tools to identify protein folding and assembly mechanisms that contribute to synaptic strengthening. We are equally interested in elucidating how these induced changes are spatially maintained in the activated synaptic compartments to establish functional units for information storage.