A while back, at a local blood drive, I was surprised (and admittedly a little relieved) to learn that I’m not eligible to donate blood in Austria. I grew up in the UK during the BSE or “mad cow disease” crisis, and in the late 1990s/early 2000s many countries stopped taking blood donations from individuals who spent time in the UK during the crisis. Transmission of infectious prions through blood transfusion has been documented in a handful of CJD (Creutzfeldt-Jakob disease) cases. And prions can stick around undetected for decades.
But what are prions? In essence, they are misfolded proteins that can induce misfolding in their normal counterparts – hence their infectivity. In the case of BSE (and the human equivalent CJD), the normal prion protein, PrPC, is converted to the misfolded and aggregated form, PrPSc. Recent research suggests that other neurodegenerative diseases (like Alzheimer’s and Parkinson’s) also involve prion-like mechanisms. But disease involving PrP is unusual in that it causes very rapid neurodegeneration – on average, a patient will die within five months of the first symptoms. For other neurodegenerative diseases, the clinical course often spans years or even decades.
What’s responsible for this difference? Intriguingly, there’s evidence that the rapid neurodegeneration in prion disease is not directly caused by aggregated PrPSc but requires normal PrPC. A new paper in Science Advances presents the first direct in vivo evidence that the unstructured and soluble N-terminal region of PrPC causes rapid and lethal neurodegeneration. The authors propose that the interaction between PrPSc and PrPC exposes the normally hidden N-terminal region and that the resulting rapid neurodegeneration is distinct from the slower aggregation-driven toxicity seen in other diseases like Alzheimer’s.
Thankfully, CJD cases linked to the BSE crisis are now virtually non-existent and several countries have lifted the blood donation ban (e.g., the FDA lifted the US ban in 2022). Nonetheless, prion disease (either sporadic or genetic) remains, affecting 300 people in the US annually, and there is no preventative, treatment, or cure. Perhaps the generative AI methods for designing binders to intrinsically disordered regions/proteins (recently published by David Baker’s lab) could be used to target the unstructured N-terminal region of PrP. Indeed, the Baker lab has designed a PrP binder, albeit targeting a different part of the protein.
Soluble N-terminal region of prion protein causes rapid neurodegeneration in prion disease
In Science Advances, 8 August 2025
From the group of Jiyan Ma at the Chinese Institute for Brain Research
Snippet by Katrina Woolcock
Image credit: Figure 6 from Yan et al. cited above (CC BY-NC)