Deciphering the cellular mechanism of seeded prion aggregation in neuronal cells

Prion diseases, transmissible diseases of the brain, affect animals and humans alike and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. Although prions, the infectious pathogens of prion diseases have been thoroughly characterised over recent decades, we still have not found the cellular mechanism by which they propagate in neuronal cells.

While prions are thought to replicate by conversion of the cellular prion protein (PrPc), a protein expressed on the surface of neurons, to disease-associated conformers of itself, the cellular site and the molecular mechanism of replication remain enigmatic.

Our preliminary data present the first molecular clues on how new aggregates of disease-associated PrP (PrPd) arise at the plasma membrane of neuronal cells. A breakthrough in the detection of PrPd variants enabled us to distinguish intracellular from extracellular PrPd aggregates. This helped us to infer that the assembly and growth of fibrillar PrPd aggregates at the plasma membrane is driven by aggregation seeds from inside the cell.

Importantly, inhibition and stimulation of the transport of these seeds to the plasma membrane prevented and accelerated fibril growth, respectively.

Together with Prof Sharon Tooze, an expert in protein secretion from the Francis Crick Institute, we plan to investigate the molecular mechanism on how the intracellular pool of PrPd reaches the plasma membrane. This is of great importance, since our preliminary data suggest inhibiting the transport of PrPd on its way to the plasma membrane may block the generation of prions.