Glycogen: the missing link in neuronal autophagy?

Onkar, Akanksha; Sheshadri, Deepashree; Ganesh, Subramaniam

doi:10.1080/15548627.2020.1802090

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…Accumulating evidence has indicated that metabolic changes in neurons associate with brain dysfunction ( Mlody et al, 2016 ; Diaz-Garcia et al, 2017 ; Onkar et al, 2020 ; Rickman et al, 2020 ; Bonvento and Bolanos, 2021 ; Li et al, 2021 ). On the other hand, not a lot has been explored for how glia react to neuronal challenges from a metabolic view.…”

Section: Resultsmentioning

confidence: 99%

Profiling neurotransmitter-evoked glial responses by RNA-sequencing analysis

Wang,

2023

Front. Neural Circuits

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Fundamental properties of neurons and glia are distinctively different. Neurons are excitable cells that transmit information, whereas glia have long been considered as passive bystanders. Recently, the concept of tripartite synapse is proposed that glia are structurally and functionally incorporated into the synapse, the basic unit of information processing in the brains. It has then become intriguing how glia actively communicate with the presynaptic and postsynaptic compartments to influence the signal transmission. Here we present a thorough analysis at the transcriptional level on how glia respond to different types of neurotransmitters. Adult fly glia were purified from brains incubated with different types of neurotransmitters ex vivo. Subsequent RNA-sequencing analyses reveal distinct and overlapping patterns for these transcriptomes. Whereas Acetylcholine (ACh) and Glutamate (Glu) more vigorously activate glial gene expression, GABA retains its inhibitory effect. All neurotransmitters fail to trigger a significant change in the expression of their synthesis enzymes, yet Glu triggers increased expression of neurotransmitter receptors including its own and nAChRs. Expressions of transporters for GABA and Glutamate are under diverse controls from DA, GABA, and Glu, suggesting that the evoked intracellular pathways by these neurotransmitters are interconnected. Furthermore, changes in the expression of genes involved in calcium signaling also functionally predict the change in the glial activity. Finally, neurotransmitters also trigger a general metabolic suppression in glia except the DA, which upregulates a number of genes involved in transporting nutrients and amino acids. Our findings fundamentally dissect the transcriptional change in glia facing neuronal challenges; these results provide insights on how glia and neurons crosstalk in a synaptic context and underlie the mechanism of brain function and behavior.

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Section: Resultsmentioning

confidence: 99%

Profiling neurotransmitter-evoked glial responses by RNA-sequencing analysis

Wang,

2023

Front. Neural Circuits

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“…Glycogen accumulation has been observed in the neurons subjected to various stressors, including oxidative stress ( Saez et al, 2014 ; Wit et al, 2013 ; Puri et al, 2011 ; Onkar et al, 2020 ). Moreover, the lifespan of organisms is inversely correlated with the increased oxidative damage and ROS levels ( Sohal and Orr, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

Alterations in brain glycogen levels influence life-history traits and reduce the lifespan in female Drosophila melanogaster

2021

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Sexual dimorphism in lifespan, wherein females outlive males, is evident across all animal taxa. The longevity difference between sexes is controlled by multiple physiological processes with complex relationships to one another. In recent years, glycogen, the storage form of glucose, has been shown to cause rapid aging upon forced synthesis in healthy neurons. Glycogen in the form of corpora amylacea in the aging brain is also widely reported. While these studies did suggest a novel role for glycogen in aging, most of them have focused on pooled samples, and have not looked at sex-specific effects, if any. Given the widespread occurrence of sex-biased expression of genes and the underlying physiology, it is important to look at the sex-specific effect of metabolic processes. In the present study, using transgenic fly lines for the human glycogen synthase, we investigated the sex-specific effect of glycogen on stress resistance, fitness, and survival. We demonstrate that Drosophila females with altered levels of glycogen in the brain display a shortened lifespan, increased resistance to starvation, and higher oxidative stress than male flies. The present study thus provides a novel insight into the sex-specific effect of glycogen in survival and aging and how differences in metabolic processes could contribute to sex-specific traits.

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“…Intriguingly, unlike liver and muscle, which store significant amounts of glycogen, the glycogen content in the brain is minimal, the majority of it primarily being stored in astrocytes ( Pellerin and Magistretti, 1994 ; Obel et al, 2012 ; Saez et al, 2014 ). Thus, excessive accumulation of brain glycogen in pathological neurodegenerative conditions indicates the alterations in the glycogen metabolic pathways, which could either be the cause or the consequence of abnormal neuronal physiology and function ( Rai and Ganesh, 2019 ; Onkar et al, 2020 ; Sheshadri et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…A small number of emerging reports have proposed a causal role of neuronal glycogen in stress response, synaptic plasticity, aging and neurodegeneration. For example, neuronal glycogen, either as a biomolecule or as a readout of the activated glycogen synthesis machinery, has been proposed to have neuroprotective roles under physiological stress conditions ( Onkar et al, 2020 ). Glycogen is the energy source mobilized to prevent neuronal death from hypoxia, ischemia, hypoglycemia, endoplasmic reticulum stress and oxidative stress ( Hossain et al, 2014 ; Saez et al, 2014 ; López-Ramos et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Increase in brain glycogen levels ameliorates Huntington's disease phenotype and rescues neurodegeneration in Drosophila

Onkar,

Sheshadri,

Rai

et al. 2023

Disease Models &Amp; Mechanisms

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Under normal physiological conditions, the mammalian brain contains very little glycogen, most of which is stored in astrocytes. However, the aging brain and subareas of the brain in patients with neurodegenerative disorders tend to accumulate glycogen, the cause and significance of which remain largely unexplored. Using cellular models, we have recently demonstrated a neuroprotective role for neuronal glycogen and glycogen synthase in the context of Huntington's disease. To gain insight into the role of brain glycogen in regulating proteotoxicity, we utilized a Drosophila model of Huntington's disease in which glycogen synthase was either knocked down or expressed ectopically. Enhancing glycogen synthesis in the brains of flies with Huntington's disease decreased mutant Huntingtin aggregation and reduced oxidative stress by activating auto-lysosomal functions. Further, the overexpression of glycogen synthase in the brain rescues photoreceptor degeneration, improves locomotor deficits, and increases fitness traits in Huntington's disease model. We thus provide in vivo evidence for the neuroprotective functions of glycogen synthase and glycogen in neurodegenerative conditions and their role in the neuronal autophagy process.

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Glycogen: the missing link in neuronal autophagy?

Cited by 6 publications

References 27 publications

Profiling neurotransmitter-evoked glial responses by RNA-sequencing analysis

Profiling neurotransmitter-evoked glial responses by RNA-sequencing analysis

Alterations in brain glycogen levels influence life-history traits and reduce the lifespan in female Drosophila melanogaster

Increase in brain glycogen levels ameliorates Huntington's disease phenotype and rescues neurodegeneration in Drosophila

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