The N-terminus of the prion protein is a toxic effector regulated by the C-terminus
Abstract
PrPC, the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrPSc, the infectious isoform, but how this occurs is mysterious. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrPC functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain. Anti-PrP antibodies targeting epitopes in the C-terminal domain induce currents, and cause degeneration of dendrites on murine hippocampal neurons, effects that entirely dependent on the effector function of the N-terminus. NMR experiments demonstrate intramolecular docking between N- and C-terminal domains of PrPC, revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrPC.
Article and author information
Author details
Funding
National Institutes of Health (R01 NS065244)
- Bei Wu
- Alex J McDonald
- Celeste B Rich
- David A Harris
National Institutes of Health (R01 GM065790)
- Kathleen Markham
- Glenn L Millhauser
National Institutes of Health (GM104316)
- Kyle P Mchugh
- David W Colby
National Science Foundation (Grant 1454508)
- Kyle P Mchugh
- David W Colby
German Research Foundation ((TA 167/6))
- Jörg Tatzelt
N.I.H. R01 NS065244 to D.A.H had a role in study design, data collection and interpretation.N.I.H. R01 GM065790 to G.L.M. had a role in data collection.N.I.H. GM104316 to D.W.C. and N.S.F. grant 1454508 to D.W.C. had a role in data collection.German Research Foundation (TA 167/6) to J.T. had a role in data collection.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#AN14997) of Boston University.
Copyright
© 2017, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Mice lacking two neuropeptides thought to be essential for processing pain show no change in how they respond to a wide range of harmful stimuli.
-
- Neuroscience
People selectively help others based on perceptions of their merit or need. Here, we develop a neurocomputational account of how these social perceptions translate into social choice. Using a novel fMRI social perception task, we show that both merit and need perceptions recruited the brain’s social inference network. A behavioral computational model identified two non-exclusive mechanisms underlying variance in social perceptions: a consistent tendency to perceive others as meritorious/needy (bias) and a propensity to sample and integrate normative evidence distinguishing high from low merit/need in other people (sensitivity). Variance in people’s merit (but not need) bias and sensitivity independently predicted distinct aspects of altruism in a social choice task completed months later. An individual’s merit bias predicted context-independent variance in people’s overall other-regard during altruistic choice, biasing people toward prosocial actions. An individual’s merit sensitivity predicted context-sensitive discrimination in generosity toward high and low merit recipients by influencing other- and self-regard during altruistic decision-making. This context-sensitive perception–action link was associated with activation in the right temporoparietal junction. Together, these findings point toward stable, biologically based individual differences in perceptual processes related to abstract social concepts like merit, and suggest that these differences may have important behavioral implications for an individual’s tendency toward favoritism or discrimination in social settings.