Neurodegenerative diseases are associated with the aberrant folding of cellular proteins into highly ordered aggregates. Experimental evidence suggests that intercellularly transmitted protein aggregates can act as templates that induce the conformational transition of normally soluble protein into abnormally folded isoforms. This behavior is reminiscent of prions, infectious agents devoid of coding nucleic acid that cause transmissible spongiform encephalopathies in mammals. Our laboratory focuses on the molecular and cellular mechanisms involved in prion formation. We are particularly interested in cellular pathways involved in intercellular aggregate dissemination.

Conversion of normally soluble proteins into highly ordered aggregates is a hallmark of neurodegenerative diseases. Prion diseases or transmissible spongiform encephalopathies (TSE) are associated with misfolding of the cellular prion protein into infectious, self-templating entities. Prions replicate by converting monomeric prion protein into an infectious, aggregated isoform, capable of spreading within the affected host and between individuals.

Interestingly, aggregates with comparable propagation strategies have also been identified in lower eukaryotes where they induce heritable changes in progeny cells. Surprisingly, domains that compositionally resemble prototype yeast prion domains are abundant in the mammalian proteome. Aggregation of human proteins with so-called “prion-like domains” has been linked to several neurodegenerative diseases. If prion-like domains could confer true prion activities such as aggregate multiplication and spreading is so far unknown. Aim of our work is to understand general mechanisms of prion formation, clearance and intercellular dissemination. We employ high throughput cell-based assays, organotypic slice cultures and mouse models to characterize pathways involved in the replication of TSE agents and cytosolic proteins with prion-like domains.