Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the periphery
- The University of Sydney, Australia
- Sidra Medicine, Qatar
- St Vincent's Hospital, Australia
- West Virginia University, United States
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)
-
Data from: Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the peripheryDryad Digital Repository, 10.5061/dryad.hp60p89.
Article and author information
Author details
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
-
- 2,564
- views
-
- 390
- downloads
-
- 38
- 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)
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
Further reading
-
- Neuroscience
Substance-induced social behavior deficits dramatically worsen the clinical outcome of substance use disorders; yet, the underlying mechanisms remain poorly understood. Herein, we investigated the role for the corticotropin-releasing factor receptor 1 (CRF1) in the acute sociability deficits induced by morphine and the related activity of oxytocin (OXY)- and arginine-vasopressin (AVP)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN). For this purpose, we used both the CRF1 receptor-preferring antagonist compound antalarmin and the genetic mouse model of CRF1 receptor-deficiency. Antalarmin completely abolished sociability deficits induced by morphine in male, but not in female, C57BL/6J mice. Accordingly, genetic CRF1 receptor-deficiency eliminated morphine-induced sociability deficits in male mice. Ex vivo electrophysiology studies showed that antalarmin also eliminated morphine-induced firing of PVN neurons in male, but not in female, C57BL/6J mice. Likewise, genetic CRF1 receptor-deficiency reduced morphine-induced firing of PVN neurons in a CRF1 gene expression-dependent manner. The electrophysiology results consistently mirrored the behavioral results, indicating a link between morphine-induced PVN activity and sociability deficits. Interestingly, in male mice antalarmin abolished morphine-induced firing in neurons co-expressing OXY and AVP, but not in neurons expressing only AVP. In contrast, in female mice antalarmin did not affect morphine-induced firing of neurons co-expressing OXY and AVP or only OXY, indicating a selective sex-specific role for the CRF1 receptor in opiate-induced PVN OXY activity. The present findings demonstrate a major, sex-linked, role for the CRF1 receptor in sociability deficits and related brain alterations induced by morphine, suggesting new therapeutic strategy for opiate use disorders.
-
- Neuroscience
When observing others’ behaviors, we continuously integrate their movements with the corresponding sounds to enhance perception and develop adaptive responses. However, how the human brain integrates these complex audiovisual cues based on their natural temporal correspondence remains unclear. Using electroencephalogram (EEG), we demonstrated that rhythmic cortical activity tracked the hierarchical rhythmic structures in audiovisually congruent human walking movements and footstep sounds. Remarkably, the cortical tracking effects exhibit distinct multisensory integration modes at two temporal scales: an additive mode in a lower-order, narrower temporal integration window (step cycle) and a super-additive enhancement in a higher-order, broader temporal window (gait cycle). Furthermore, while neural responses at the lower-order timescale reflect a domain-general audiovisual integration process, cortical tracking at the higher-order timescale is exclusively engaged in the integration of biological motion cues. In addition, only this higher-order, domain-specific cortical tracking effect correlates with individuals’ autistic traits, highlighting its potential as a neural marker for autism spectrum disorder. These findings unveil the multifaceted mechanism whereby rhythmic cortical activity supports the multisensory integration of human motion, shedding light on how neural coding of hierarchical temporal structures orchestrates the processing of complex, natural stimuli across multiple timescales.
