Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain

  1. Federico Salas-Lucia
  2. Csaba Fekete
  3. Richárd Sinko
  4. Péter Egri
  5. Kristóf Rada
  6. Yvette Ruska
  7. Balázs Gereben  Is a corresponding author
  8. Antonio Bianco  Is a corresponding author
  1. University of Chicago Medical Center, United States
  2. Institute of Experimental Medicine, Hungary
  3. University of Chicago, United States

Abstract

The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3's active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for supplementary figures 2

Article and author information

Author details

  1. Federico Salas-Lucia

    Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4141-5790
  2. Csaba Fekete

    Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8206-562X
  3. Richárd Sinko

    Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    No competing interests declared.
  4. Péter Egri

    Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    No competing interests declared.
  5. Kristóf Rada

    Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    No competing interests declared.
  6. Yvette Ruska

    Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
    Competing interests
    No competing interests declared.
  7. Balázs Gereben

    Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, Budapest, Hungary
    For correspondence
    gereben.balazs@koki.mta.hu
    Competing interests
    No competing interests declared.
  8. Antonio Bianco

    Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, United States
    For correspondence
    abianco1@uchicago.edu
    Competing interests
    Antonio Bianco, Consultant fees: AbbVie, Synthonics, Sention, Thyron, Accella.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7737-6813

Funding

The Hungarian National Brain Research Program 2 (NRDIO K125247)

  • Csaba Fekete

National Institute of Diabetes and Digestive and Kidney Diseases (DK58538)

  • Balázs Gereben

National Institute of Diabetes and Digestive and Kidney Diseases (DK58538,DK65055)

  • Antonio Bianco

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Rauf Latif, Icahn School of Medicine at Mount Sinai, United States

Ethics

Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee at the University of Chicago (#72577) or by the Animal Welfare Committee at the Institute of ExperimentalMedicine and followed the American Thyroid Association Guide to investigating TH economy and action in rodents and cell models (52).

Version history

  1. Received: August 13, 2022
  2. Preprint posted: August 18, 2022 (view preprint)
  3. Accepted: May 18, 2023
  4. Accepted Manuscript published: May 19, 2023 (version 1)
  5. Version of Record published: June 5, 2023 (version 2)

Copyright

© 2023, Salas-Lucia 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.

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  1. Federico Salas-Lucia
  2. Csaba Fekete
  3. Richárd Sinko
  4. Péter Egri
  5. Kristóf Rada
  6. Yvette Ruska
  7. Balázs Gereben
  8. Antonio Bianco
(2023)
Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain
eLife 12:e82683.
https://doi.org/10.7554/eLife.82683

Share this article

https://doi.org/10.7554/eLife.82683

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