The N-terminus of the prion protein is a toxic effector regulated by the C-terminus

  1. Bei Wu
  2. Alex J McDonald
  3. Kathleen Markham
  4. Celeste B Rich
  5. Kyle P Mchugh
  6. Jörg Tatzelt
  7. David W Colby
  8. Glenn L Millhauser
  9. David A Harris  Is a corresponding author
  1. Boston University School of Medicine, United States
  2. University of California, Santa Cruz, United States
  3. University of Delaware, United States
  4. Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Germany

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

  1. Bei Wu

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alex J McDonald

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kathleen Markham

    Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Celeste B Rich

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kyle P Mchugh

    Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jörg Tatzelt

    Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5017-5528
  7. David W Colby

    Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Glenn L Millhauser

    Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. David A Harris

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    For correspondence
    daharris@bu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6985-5790

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.

Metrics

  • 3,148
    views
  • 675
    downloads
  • 68
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

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)

  1. Bei Wu
  2. Alex J McDonald
  3. Kathleen Markham
  4. Celeste B Rich
  5. Kyle P Mchugh
  6. Jörg Tatzelt
  7. David W Colby
  8. Glenn L Millhauser
  9. David A Harris
(2017)
The N-terminus of the prion protein is a toxic effector regulated by the C-terminus
eLife 6:e23473.
https://doi.org/10.7554/eLife.23473

Share this article

https://doi.org/10.7554/eLife.23473

Further reading

    1. Neuroscience
    Poortata Lalwani, Thad Polk, Douglas D Garrett
    Research Article

    Moment-to-moment neural variability has been shown to scale positively with the complexity of stimulus input. However, the mechanisms underlying the ability to align variability to input complexity are unknown. Using a combination of behavioral methods, computational modeling, fMRI, MR spectroscopy, and pharmacological intervention, we investigated the role of aging and GABA in neural variability during visual processing. We replicated previous findings that participants expressed higher variability when viewing more complex visual stimuli. Additionally, we found that such variability modulation was associated with higher baseline visual GABA levels and was reduced in older adults. When pharmacologically increasing GABA activity, we found that participants with lower baseline GABA levels showed a drug-related increase in variability modulation while participants with higher baseline GABA showed no change or even a reduction, consistent with an inverted-U account. Finally, higher baseline GABA and variability modulation were jointly associated with better visual-discrimination performance. These results suggest that GABA plays an important role in how humans utilize neural variability to adapt to the complexity of the visual world.

    1. Neuroscience
    François Osiurak, Giovanni Federico ... Mathieu Lesourd
    Research Article

    Our propensity to materiality, which consists in using, making, creating, and passing on technologies, has enabled us to shape the physical world according to our ends. To explain this proclivity, scientists have calibrated their lens to either low-level skills such as motor cognition or high-level skills such as language or social cognition. Yet, little has been said about the intermediate-level cognitive processes that are directly involved in mastering this materiality, that is, technical cognition. We aim to focus on this intermediate level for providing new insights into the neurocognitive bases of human materiality. Here, we show that a technical-reasoning process might be specifically at work in physical problem-solving situations. We found via two distinct neuroimaging studies that the area PF (parietal F) within the left parietal lobe is central for this reasoning process in both tool-use and non-tool-use physical problem-solving and can work along with social-cognitive skills to resolve day-to-day interactions that combine social and physical constraints. Our results demonstrate the existence of a specific cognitive module in the human brain dedicated to materiality, which might be the supporting pillar allowing the accumulation of technical knowledge over generations. Intensifying research on technical cognition could nurture a comprehensive framework that has been missing in fields interested in how early and modern humans have been interacting with the physical world through technology, and how this interaction has shaped our history and culture.