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.

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).

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.

Metrics

  • 1,094
    views
  • 177
    downloads
  • 12
    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. 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

Further reading

    1. Medicine
    Jeong-Oh Shin, Jong-Bin Lee ... Jin-Woo Kim
    Research Article

    This study investigates the effects of two parathyroid hormone (PTH) analogs, rhPTH(1-34) and dimeric R25CPTH(1-34), on bone regeneration and osseointegration in a postmenopausal osteoporosis model using beagle dogs. Twelve osteoporotic female beagles were subjected to implant surgeries and assigned to one of three groups: control, rhPTH(1-34), or dimeric R25CPTH(1-34). Bone regeneration and osseointegration were evaluated after 10 weeks using micro-computed tomographic (micro-CT), histological analyses, and serum biochemical assays. Results showed that the rhPTH(1-34) group demonstrated superior improvements in bone mineral density, trabecular architecture, and osseointegration compared to controls, while the dimeric R25CPTH(1-34) group exhibited similar, though slightly less pronounced, anabolic effects. Histological and TRAP assays indicated both PTH analogs significantly enhanced bone regeneration, especially in artificially created bone defects. The findings suggest that both rhPTH(1-34) and dimeric R25CPTH(1-34) hold potential as therapeutic agents for promoting bone regeneration and improving osseointegration around implants in osteoporotic conditions, with implications for their use in bone-related pathologies and reconstructive surgeries.

    1. Medicine
    2. Neuroscience
    Sophie Leclercq, Hany Ahmed ... Nathalie Delzenne
    Research Article

    Background:

    Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits.

    Methods:

    In this study, we investigated the impact of severe AUD (sAUD), and of a 3-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal.

    Results:

    We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine, and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in postmortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue.

    Conclusions:

    Our data allow the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets arising in the management of neuropsychiatric diseases such as sAUD.

    Funding:

    Gut2Behave project was initiated from ERA-NET NEURON network (Joint Transnational Call 2019) and was financed by Academy of Finland, French National Research Agency (ANR-19-NEUR-0003-03) and the Fonds de la Recherche Scientifique (FRS-FNRS; PINT-MULTI R.8013.19, Belgium). Metabolomics analysis of the TSDS samples was supported by grant from the Finnish Foundation for Alcohol Studies.