The Biophysical Determinants of Prion Neuroinvasion

Prions naturally transmit to other individuals as infectious pathogens and have led to large scale epidemics, for example, as occurred during the bovine spongiform encephalopathy (BSE) epidemic. In humans, prions have been transmitted iatrogenically through the transplantation of dura mater grafts and cornea from prion‐infected donors. Most cases of natural prion transmission follow a peripheral exposure and prions spread into the CNS in a process known as neuroinvasion. This ability of most prions to shuttle in and out of the CNS is remarkable and not described for other amyloidogenic proteins. Using mouse models, we have found that certain prion aggregates rarely invade the CNS following intraperitoneal or intra‐tongue inoculation, yet accumulate in extraneural organs, leading to lifelong subclinical carriers of infectious prions. Intriguingly, these poorly neuroinvasive prions are fibrillar, which are uncommon structures in prion disease, as most prions form oligomers. We found that reducing the prion aggregate size markedly impacts the neuroinvasive ability of fibrillar prions, suggesting that size plays an important role in prion neuroinvasion. Additionally, we have found that the intravenous route is surprisingly efficient for fibrillar prion entry into the CNS, which may help explain how human‐to‐human transmission of variant‐Creutzfeldt‐Jakob disease prions occurred following blood transfusion. Taken together, these results indicate that aggregate size and route of exposure are major determinants that impact the ability of a prion to neuroinvade. Support or Funding Information NIH R01NS076896