Study reveals new detail on how prions replicate in neuronal cells

Prions, the disease-causing proteins of prion diseases, are thought to replicate in cells by a self-generating mechanism, giving rise to more copies of rogue proteins. While scientists widely agree that misfolded versions of the prion protein drive this phenomenon, the detailed cellular mechanisms orchestrating this process remain a captivating enigma.

A new study has shed light on the intricate mode of cellular prion propagation. Dr Peter Klöhn and his team at the MRC Prion Unit have revealed that abnormal versions of the prion protein accumulate on the cell surface of neuronal cells, forming aggregates that resemble fibrils. These protein fibrils not only elongate but also offer evidence of self-assembly. Intriguingly, the absence of fibrillar aggregates inside the cells raises a compelling question about how the fibril growth on the cell surface is sustained.

The research team pinpointed shorter versions of the protein within cells, forming compact, spot-like patches without developing fibrils. Subsequent findings indicated that these shortened abnormal prion proteins reach the plasma membrane through small transport carriers. Interestingly, when the electrical charge of the neuronal membrane changed, as it usually does when nerve cells fire, it led to self-aggregation at the cell surface.

Dr Klöhn said:

“Our study is providing a key insight into the importance of proteolytic changes. It suggests that the templates which drive misfolding are shortened versions of the prion protein. The transport of such templates to the plasma membrane through tiny transport carriers is closing the loop of self-assembly by a yet uncharacterised mechanism. Intriguingly, seeds and self-assembled abnormal PrP fibrils are spatially separated which may provide opportunities for therapeutic intervention of prion propagation.”

The study further shows that the entry of prions into neuronal cells is dependent on functional Cdc42 and dynamins. Intriguingly, depletion of the genes that encode these proteins effectively blocks prion uptake.

Co-lead author, Dr Juan Ribes added:

“Having developed new biomolecular tools to study self-assembly, we are now eager to further investigate the biology of prion protein conversion. Our goal is to figure out ways to block prion propagation in neuronal cells.”

*Figure: Two cell types, primary astrocytes and neuroblastoma cells, infected with prions show characteristic fibrils (in green), denoted by hatched arrows and spotty patches of shortened protein in red, denoted by long straight arrows.

Links:

• Read the paper in Nature Communications
• Dr Peter Klöhn’s academic profile
• Dr Juan Ribes's academic profile
• MRC Prion Unit, UCL Institute of Prion Diseases