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

  • 3,047
    views
  • 660
    downloads
  • 64
    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
    Nicolas Langer, Maurice Weber ... Ce Zhang
    Tools and Resources

    Memory deficits are a hallmark of many different neurological and psychiatric conditions. The Rey–Osterrieth complex figure (ROCF) is the state-of-the-art assessment tool for neuropsychologists across the globe to assess the degree of non-verbal visual memory deterioration. To obtain a score, a trained clinician inspects a patient’s ROCF drawing and quantifies deviations from the original figure. This manual procedure is time-consuming, slow and scores vary depending on the clinician’s experience, motivation, and tiredness. Here, we leverage novel deep learning architectures to automatize the rating of memory deficits. For this, we collected more than 20k hand-drawn ROCF drawings from patients with various neurological and psychiatric disorders as well as healthy participants. Unbiased ground truth ROCF scores were obtained from crowdsourced human intelligence. This dataset was used to train and evaluate a multihead convolutional neural network. The model performs highly unbiased as it yielded predictions very close to the ground truth and the error was similarly distributed around zero. The neural network outperforms both online raters and clinicians. The scoring system can reliably identify and accurately score individual figure elements in previously unseen ROCF drawings, which facilitates explainability of the AI-scoring system. To ensure generalizability and clinical utility, the model performance was successfully replicated in a large independent prospective validation study that was pre-registered prior to data collection. Our AI-powered scoring system provides healthcare institutions worldwide with a digital tool to assess objectively, reliably, and time-efficiently the performance in the ROCF test from hand-drawn images.

    1. Neuroscience
    Masahiro Takigawa, Marta Huelin Gorriz ... Daniel Bendor
    Research Article

    During rest and sleep, memory traces replay in the brain. The dialogue between brain regions during replay is thought to stabilize labile memory traces for long-term storage. However, because replay is an internally-driven, spontaneous phenomenon, it does not have a ground truth - an external reference that can validate whether a memory has truly been replayed. Instead, replay detection is based on the similarity between the sequential neural activity comprising the replay event and the corresponding template of neural activity generated during active locomotion. If the statistical likelihood of observing such a match by chance is sufficiently low, the candidate replay event is inferred to be replaying that specific memory. However, without the ability to evaluate whether replay detection methods are successfully detecting true events and correctly rejecting non-events, the evaluation and comparison of different replay methods is challenging. To circumvent this problem, we present a new framework for evaluating replay, tested using hippocampal neural recordings from rats exploring two novel linear tracks. Using this two-track paradigm, our framework selects replay events based on their temporal fidelity (sequence-based detection), and evaluates the detection performance using each event's track discriminability, where sequenceless decoding across both tracks is used to quantify whether the track replaying is also the most likely track being reactivated.