The cellular proteome and its organisation are remarkably complex. An average human cell expresses around 10,000 different proteins with copy number varying from a few molecules to tens of thousands. To maintain a homeostasis, cell must carefully balance its proteome by controlling protein quality, localisation and abundance. Maintaining a healthy proteome (proteostasis) requires cells to coordinate the functions of three interconnected arms: protein synthesis and de-novo folding, quality control of existing proteins and macro complexes and protein degradation.

In our laboratory we are interested in the molecular basis of proteostasis regulation with primary focus on protein clearance pathways and its relevance in human diseases. Maintenance of cellular proteostasis requires temporally and spatially controlled degradation of regulatory and erroneous proteins. The degradation of proteins is mainly mediated by the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway. We focus on understanding how ubiquitin-proteasome system is regulated in different cellular compartments and regions. We explore how ubiquitin-proteasome system is modulated in the nucleus and how does it crosstalk with cytosolic protein degradation machinery. We are also interested in the mechanism regulating nucleocytoplasmic shuttling of the ubiquitin-proteasome system components, including the major cellular protein unfoldase VCP/p97.

Protein degradation is a key mechanism to adapt protein levels to cellular or environmental changes. Efficient protein removal is crucial to avoid accumulation of misfolded, faulty, and toxic protein species, including mutant or mislocalised proteins. The decline in protein clearance pathways is a key driver of age-related cellular dysfunction and accumulation of toxic protein species is associated with many neurodegenerative diseases, including Huntington’s, Alzheimer’s, and Parkinson’s diseases.

To investigate the cellular proteostasis we employ a variety of molecular and biochemical methods, including high-throughput CRISPR/Cas9-based screening and mass spectrometry methods. We use state-of-the-art fluorescence microscopy and cellular models of neurodegenerative diseases, including human iPSC-derived neuronal cultures and organoids.

We aim to broaden our understanding of proteostasis networks in the context of normal and diseased tissues. We expect that our results will reveal insights into pathogenesis and could facilitate new therapeutic approaches for restoring cellular proteostasis.