Research Introduction

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.

Many proteins can transition between soluble and assembled states. This is typically associated with a  change in their biochemical activities, allowing organisms to rapidly change their phenotypes.

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.

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.

We are interested in clarifying the mechanisms by which neuronal sub-compartments, synapses, are functionally individualized.