1. Neuroscience

Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the periphery

  1. Ting Zhang
  2. Ling Zhu  Is a corresponding author
  3. Michele Catherine Madigan
  4. Wei Liu
  5. Weiyong Shen
  6. Svetlana Cherepanoff
  7. Fanfan Zhou
  8. Shaoxue Zeng
  9. Jianhai Du
  10. Mark Cedric Gillies
  1. The University of Sydney, Australia
  2. Sidra Medicine, Qatar
  3. St Vincent's Hospital, Australia
  4. West Virginia University, United States
https://doi.org/10.7554/eLife.43598
Share this article
Cite this article
  1. Ting Zhang
  2. Ling Zhu
  3. Michele Catherine Madigan
  4. Wei Liu
  5. Weiyong Shen
  6. Svetlana Cherepanoff
  7. Fanfan Zhou
  8. Shaoxue Zeng
  9. Jianhai Du
  10. Mark Cedric Gillies
(2019)
Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the periphery
eLife 8:e43598.
https://doi.org/10.7554/eLife.43598
  2. Download BibTeX
  3. Download .RIS

Abstract

The human macula is more susceptible than the peripheral retina to developing blinding conditions such as age-related macular degeneration, diabetic retinopathy. A key difference between them may be the nature of their Müller cells. We found primary cultured Müller cells from macula and peripheral retina display significant morphological and transcriptomic differences. Macular Müller cells expressed more Phosphoglycerate Dehydrogenase (PHGDH, a rate-limiting enzyme in serine synthesis) than peripheral Müller cells. The serine synthesis, glycolytic and mitochondrial function were more activated in macular than peripheral Müller cells. Serine biosynthesis is critical in defending against oxidative stress. Intracellular reactive oxygen species and glutathione levels were increased in primary cultured macular Müller cells which were more susceptible to oxidative stress after inhibition of PHGDH. Our findings indicate serine biosynthesis is a critical part of the macular defence against oxidative stress and suggest dysregulation of this pathway as a potential cause of macular pathology.

Data availability

RNA sequencing data are included in the manuscript and Supplementary File. These data are also available at Dryad (https://datadryad.org/dx.doi:10.5061/dryad.hp60p89)

The following data sets were generated

Article and author information

Author details

  1. Ting Zhang

    Save Sight Institute, The University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  2. Ling Zhu

    Save Sight Institute, The University of Sydney, Sydney, Australia
    For correspondence
    ling.zhu@sydney.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0776-1630

  3. Michele Catherine Madigan

    Save Sight Institute, The University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  4. Wei Liu

    Clinical Genomics Laboratory, Sidra Medicine, Doha, Qatar
    Competing interests
    The authors declare that no competing interests exist.

  5. Weiyong Shen

    Save Sight Institute, The University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  6. Svetlana Cherepanoff

    Department of Anatomical Pathology, St Vincent's Hospital, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  7. Fanfan Zhou

    Faculty of Pharmacy, The University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  8. Shaoxue Zeng

    Save Sight Institute, The University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  9. Jianhai Du

    Department of Ophthalmology, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Mark Cedric Gillies

    Save Sight Institute, The University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Health and Medical Research Council

  • Ling Zhu
  • Weiyong Shen
  • Mark Cedric Gillies

The Ophthalmic Research Institute of Australia

  • Ling Zhu
  • Mark Cedric Gillies

National Institutes of Health

  • Jianhai Du

Lowy Medical Research Institute

  • Ting Zhang
  • Ling Zhu
  • Weiyong Shen
  • Mark Cedric Gillies

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

Ethics

Human subjects: Human retinas were obtained from post-mortem donor eyes with ethical approval from Human Research Ethics Committee of the University of Sydney (HREC#:16/282).

Copyright

© 2019, Zhang 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

  • 2,604
    views
  • 400
    downloads
  • 42
    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. Ting Zhang
  2. Ling Zhu
  3. Michele Catherine Madigan
  4. Wei Liu
  5. Weiyong Shen
  6. Svetlana Cherepanoff
  7. Fanfan Zhou
  8. Shaoxue Zeng
  9. Jianhai Du
  10. Mark Cedric Gillies
(2019)
Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the periphery
eLife 8:e43598.
https://doi.org/10.7554/eLife.43598

Share this article

https://doi.org/10.7554/eLife.43598

Categories and tags

Further reading

    1. Neuroscience

    Rhythmic circuit function is more robust to changes in synaptic than intrinsic conductances

    Zachary Fournier, Leandro M Alonso, Eve Marder
    Research Article

    Circuit function results from both intrinsic conductances of network neurons and the synaptic conductances that connect them. In models of neural circuits, different combinations of maximal conductances can give rise to similar activity. We compared the robustness of a neural circuit to changes in their intrinsic versus synaptic conductances. To address this, we performed a sensitivity analysis on a population of conductance-based models of the pyloric network from the crustacean stomatogastric ganglion (STG). The model network consists of three neurons with nine currents: a sodium current (Na), three potassium currents (Kd, KCa, KA), two calcium currents (CaS and CaT), a hyperpolarization-activated current (H), a non-voltage-gated leak current (leak), and a neuromodulatory current (MI). The model cells are connected by seven synapses of two types, glutamatergic and cholinergic. We produced one hundred models of the pyloric network that displayed similar activities with values of maximal conductances distributed over wide ranges. We evaluated the robustness of each model to changes in their maximal conductances. We found that individual models have different sensitivities to changes in their maximal conductances, both in their intrinsic and synaptic conductances. As expected, the models become less robust as the extent of the changes increases. Despite quantitative differences in their robustness, we found that in all cases, the model networks are more sensitive to the perturbation of their intrinsic conductances than their synaptic conductances.

    1. Neuroscience

    Cognition: When working memory works for our goals

    Jacob A Miller
    Insight

    When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.

    1. Neuroscience

    Cerebellar Purkinje cells control posture in larval zebrafish (Danio rerio)

    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.