Deciphering the cellular mechanism of seeded prion aggregation in neuronal cells
Award Number
BB/V001310/1Status / Stage
ActiveDates
1 June 2021 -31 May 2024
Duration (calculated)
02 years 11 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£413,375.00Funder/Grant study page
BBSRC UKRIContracted Centre
University College LondonContracted Centre Webpage
Principal Investigator
Dr Peter KloehnPI Contact
p.kloehn@prion.ucl.ac.ukWHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 374 |
|---|---|
| Researcher | Reside Team |
| Published | 12/06/2023 |
Data
| Award Number | BB/V001310/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20210601 |
| End Date | 20240531 |
| Duration (calculated) | 02 years 11 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University College London |
| Contracted Centre Webpage | |
| Funding Amount | £413,375.00 |
Abstract
Prions, the infectious pathogens of prion diseases are thought to arise by template-assisted conversion of the cellular prion protein, but the underpinning cellular mechanism of this pathogenic process remains unknown. While a growing body of data suggests that self-templating assemblies of protein aggregates are the basis of many, if not all neurodegenerative diseases, such “prion-like” mechanisms are ill-defined, which underscores the importance to better define common pathogenic mechanisms. We provide first evidence of how prions replicate in neuronal cells and propose, in collaboration with Sharon Tooze, an expert in protein secretion from the Francis Crick Institute, a comprehensive work plan to gain further evidence in support of our preliminary data. Our results suggest that aggregates of disease-associated PrP (PrPd) segregate into the protein secretory pathway and reach the plasma membrane, where they convert PrPc to full-length (FL-) PrPd. Formation of long rod-like FL-PrPd fibrils, detected by anti-PrP antibodies against FL-PrP, can be blocked by lowering cellular cholesterol and stimulated by dissipation of the vesicular pH gradient, a treatment that concomitantly led to an increase in prion release. Owing to evidence that neuropeptides and prohormones are sorted into the regulated secretory pathway by virtue of protein aggregation, we will address the important questions whether (i) prions are sorted into the secretory pathway by default and (ii) whether the cellular environment of vesicle biogenesis favours misfolding of aggregation-prone proteins. This project contributes to a better characterisation of seeded aggregation and may provide guiding principles to characterise prion-like mechanisms.
Aims
Our aim to scrutinise how rogue prion proteins enter secretory pathways may not only explain the rapid dissemination of prions in the brain, but may also help to identify critical control mechanisms for entry into secretory pathways. Our collaboration with Sharon Tooze, an eminent expert in the exocytosis field will help to excel knowledge transfer and exchange with basic research. Prion disease research: Our aim to identify the cellular mechanism of seeded prion aggregation will greatly benefit the prion field