Enhanced neuroinvasion by smaller, soluble prions

Cyrus Bett, Jessica Lawrence, Timothy D. Kurt, Christina Orru, Patricia Aguilar-Calvo, Anthony Kincaid, Witold K. Surewicz, Byron Caughey, Chengbiao Wu, Christina J. Sigurdson

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Infectious prion aggregates can propagate from extraneural sites into the brain with remarkable efficiency, likely transported via peripheral nerves. Yet not all prions spread into the brain, and the physical properties of a prion that is capable of transit within neurons remain unclear. We hypothesized that small, diffusible aggregates spread into the CNS via peripheral nerves. Here we used a structurally diverse panel of prion strains to analyze how the prion conformation impacts transit into the brain. Two prion strains form fibrils visible ultrastructurally in the brain in situ, whereas three strains form diffuse, subfibrillar prion deposits and no visible fibrils. The subfibrillar strains had significantly higher levels of soluble prion aggregates than the fibrillar strains. Primary neurons internalized both the subfibrillar and fibril-forming prion strains by macropinocytosis, and both strain types were transported from the axon terminal to the cell body in vitro. However in mice, only the predominantly soluble, subfibrillar prions, and not the fibrillar prions, were efficiently transported from the tongue to the brain. Sonicating a fibrillar prion strain increased the solubility and enabled prions to spread into the brain in mice, as evident by a 40% increase in the attack rate, indicating that an increase in smaller particles enhances prion neuroinvasion. Our data suggest that the small, highly soluble prion particles have a higher capacity for transport via nerves. These findings help explain how prions that predominantly assemble into subfibrillar states can more effectively traverse into and out of the CNS, and suggest that promoting fibril assembly may slow the neuron-to-neuron spread of protein aggregates.

Original languageEnglish (US)
Number of pages1
JournalActa neuropathologica communications
Volume5
Issue number1
DOIs
StatePublished - Apr 21 2017

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Prions
Brain
Neurons
Peripheral Nerves
Presynaptic Terminals
Tongue
Solubility

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Bett, C., Lawrence, J., Kurt, T. D., Orru, C., Aguilar-Calvo, P., Kincaid, A., ... Sigurdson, C. J. (2017). Enhanced neuroinvasion by smaller, soluble prions. Acta neuropathologica communications, 5(1). https://doi.org/10.1186/s40478-017-0430-z

Enhanced neuroinvasion by smaller, soluble prions. / Bett, Cyrus; Lawrence, Jessica; Kurt, Timothy D.; Orru, Christina; Aguilar-Calvo, Patricia; Kincaid, Anthony; Surewicz, Witold K.; Caughey, Byron; Wu, Chengbiao; Sigurdson, Christina J.

In: Acta neuropathologica communications, Vol. 5, No. 1, 21.04.2017.

Research output: Contribution to journalArticle

Bett, C, Lawrence, J, Kurt, TD, Orru, C, Aguilar-Calvo, P, Kincaid, A, Surewicz, WK, Caughey, B, Wu, C & Sigurdson, CJ 2017, 'Enhanced neuroinvasion by smaller, soluble prions', Acta neuropathologica communications, vol. 5, no. 1. https://doi.org/10.1186/s40478-017-0430-z
Bett, Cyrus ; Lawrence, Jessica ; Kurt, Timothy D. ; Orru, Christina ; Aguilar-Calvo, Patricia ; Kincaid, Anthony ; Surewicz, Witold K. ; Caughey, Byron ; Wu, Chengbiao ; Sigurdson, Christina J. / Enhanced neuroinvasion by smaller, soluble prions. In: Acta neuropathologica communications. 2017 ; Vol. 5, No. 1.
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