Glia-neuron coupling via a bipartite sialylation pathway promotes neural transmission and stress tolerance in Drosophila

  1. Hilary Scott
  2. Boris Novikov
  3. Berrak Ugur
  4. Brooke Allen
  5. Ilya Mertsalov
  6. Pedro Monagas-Valentin
  7. Melissa Koff
  8. Sarah Baas Robinson
  9. Kazuhiro Aoki
  10. Raisa Veizaj
  11. Dirk Lefeber
  12. Michael Tiemeyer
  13. Hugo J Bellen
  14. Vladislav Panin  Is a corresponding author
  1. Texas A&M University, United States
  2. Baylor College of Medicine, United States
  3. University of Georgia, United States
  4. Radboud University Nijmegen Medical Centre, Netherlands

Abstract

Modification by sialylated glycans can affect protein functions, underlying mechanisms that control animal development and physiology. Sialylation relies on a dedicated pathway involving evolutionarily conserved enzymes, including CMP-sialic acid synthetase (CSAS) and sialyltransferase (SiaT) that mediate the activation of sialic acid and its transfer onto glycan termini, respectively. In Drosophila, CSAS and DSiaT genes function in the nervous system, affecting neural transmission and excitability. We found that these genes function in different cells: the function of CSAS is restricted to glia, while DSiaT functions in neurons. This partition of the sialylation pathway allows for regulation of neural functions via a glia-mediated control of neural sialylation. The sialylation genes were shown to be required for tolerance to heat and oxidative stress and for maintenance of the normal level of voltage-gated sodium channels. Our results uncovered a unique bipartite sialylation pathway that mediates glia-neuron coupling and regulates neural excitability and stress tolerance.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been uploaded to a public repository for Tables 1 and Supplementary Table 3

The following data sets were generated

Article and author information

Author details

  1. Hilary Scott

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  2. Boris Novikov

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  3. Berrak Ugur

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4806-8891
  4. Brooke Allen

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  5. Ilya Mertsalov

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  6. Pedro Monagas-Valentin

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  7. Melissa Koff

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  8. Sarah Baas Robinson

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  9. Kazuhiro Aoki

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  10. Raisa Veizaj

    Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  11. Dirk Lefeber

    Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  12. Michael Tiemeyer

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  13. Hugo J Bellen

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    Hugo J Bellen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5992-5989
  14. Vladislav Panin

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    For correspondence
    panin@tamu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9126-1481

Funding

National Institutes of Health (NS099409)

  • Vladislav Panin

National Institutes of Health (NS075534)

  • Vladislav Panin

TAMU-COANCYT (2012-037(S))

  • Vladislav Panin

TAMU AgriLife IHA

  • Vladislav Panin

National Institutes of Health (GM103490)

  • Michael Tiemeyer

Radboud Consortium for Glycoscience

  • Dirk Lefeber

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

Copyright

© 2023, Scott 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

  • 1,254
    views
  • 212
    downloads
  • 0
    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. Hilary Scott
  2. Boris Novikov
  3. Berrak Ugur
  4. Brooke Allen
  5. Ilya Mertsalov
  6. Pedro Monagas-Valentin
  7. Melissa Koff
  8. Sarah Baas Robinson
  9. Kazuhiro Aoki
  10. Raisa Veizaj
  11. Dirk Lefeber
  12. Michael Tiemeyer
  13. Hugo J Bellen
  14. Vladislav Panin
(2023)
Glia-neuron coupling via a bipartite sialylation pathway promotes neural transmission and stress tolerance in Drosophila
eLife 12:e78280.
https://doi.org/10.7554/eLife.78280

Share this article

https://doi.org/10.7554/eLife.78280

Further reading

    1. Biochemistry and Chemical Biology
    2. Genetics and Genomics
    Kira Breunig, Xuifen Lei ... Luiz O Penalva
    Research Article

    RNA binding proteins (RBPs) containing intrinsically disordered regions (IDRs) are present in diverse molecular complexes where they function as dynamic regulators. Their characteristics promote liquid-liquid phase separation (LLPS) and the formation of membraneless organelles such as stress granules and nucleoli. IDR-RBPs are particularly relevant in the nervous system and their dysfunction is associated with neurodegenerative diseases and brain tumor development. Serpine1 mRNA-binding protein 1 (SERBP1) is a unique member of this group, being mostly disordered and lacking canonical RNA-binding domains. We defined SERBP1’s interactome, uncovered novel roles in splicing, cell division and ribosomal biogenesis, and showed its participation in pathological stress granules and Tau aggregates in Alzheimer’s brains. SERBP1 preferentially interacts with other G-quadruplex (G4) binders, implicated in different stages of gene expression, suggesting that G4 binding is a critical component of SERBP1 function in different settings. Similarly, we identified important associations between SERBP1 and PARP1/polyADP-ribosylation (PARylation). SERBP1 interacts with PARP1 and its associated factors and influences PARylation. Moreover, protein complexes in which SERBP1 participates contain mostly PARylated proteins and PAR binders. Based on these results, we propose a feedback regulatory model in which SERBP1 influences PARP1 function and PARylation, while PARylation modulates SERBP1 functions and participation in regulatory complexes.

    1. Biochemistry and Chemical Biology
    Parnian Arafi, Sujan Devkota ... Michael S Wolfe
    Research Article

    Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer’s disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled γ-secretase enzyme-substrate and/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in a Caenorhabditis elegans model of FAD independently of Aβ production. Here, we conducted full quantitative analysis of all proteolytic events on APP substrate by γ-secretase with six additional PSEN1 FAD mutations and found that all six are deficient in multiple processing steps. However, only one of these (F386S) was deficient in certain trimming steps but not in endoproteolysis. Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled γ-secretase enzyme-substrate/intermediate complexes. The F386S mutation, however, does so only in Aβ-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of Aβ intermediates. These findings provide further evidence that FAD mutations lead to stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.