The Neuronal Overexpression of Gclc in Drosophila melanogaster Induces Life Extension With Longevity-Associated Transcriptomic Changes in the Thorax

Moskalev, Alexey; Guvatova, Zulfiya G.; Shaposhnikov, Mikhail; Lashmanova, Ekaterina; Proshkina, Ekaterina; Koval, Liubov; Zhavoronkov, Alex; Krasnov, George S.; Kudryavtseva, Anna V.

doi:10.3389/fgene.2019.00149

Cited by 9 publications

(6 citation statements)

References 87 publications

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“…Glutamate cysteine ligase (GCL) is the rate limiting enzyme in the GSH biosynthetic pathway. It has been known for some time that increasing the catalytic (GCLC) and modifying (GCLM) levels globally ( Orr et al, 2005 ) or specifically in neurons ( Moskalev et al, 2019 ) extends longevity in Drosophila by between 25 and 50%. Overexpressing GCLM increases cellular glutathione content 2-fold, protecting cells from oxidative stress ( Moskalev et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

West

Ugbode

Fort-Aznar

et al. 2020

Neurobiology of Disease

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Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B , a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2B Intron5 induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2B Intron5 . Rescue of CHMP2B Intron5 dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

West

Ugbode

Fort-Aznar

et al. 2020

Neurobiology of Disease

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“…Besides antioxidant enzymes directly involved in the detoxification of ROS, another strategy to manipulate cellular redox state in vivo is to target enzymes that provide reducing equivalents for the recycling of antioxidant systems and redox couples. For instance, overexpression of glutamate-cysteine-ligase (GCL), which catalyses the rate-limiting step in the synthesis of GSH, increased lifespan in flies [44,45]. Similarly, overexpression of glucose-6-phosphate dehydrogenase (G6PDH), an enzyme belonging to the pentose phosphate pathway (PPP) involved in the generation of NADPH, robustly extended fly lifespan [46].…”

Section: The Connection Between Oxidative Stress Redox Signalling Anmentioning

confidence: 99%

Redox signalling and ageing: insights from Drosophila

Lennicke

Cochemé

2020

Biochemical Society Transactions

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Ageing and age-related diseases are major challenges for the social, economic and healthcare systems of our society. Amongst many theories, reactive oxygen species (ROS) have been implicated as a driver of the ageing process. As by-products of aerobic metabolism, ROS are able to randomly oxidise macromolecules, causing intracellular damage that accumulates over time and ultimately leads to dysfunction and cell death. However, the genetic overexpression of enzymes involved in the detoxification of ROS or treatment with antioxidants did not generally extend lifespan, prompting a re-evaluation of the causal role for ROS in ageing. More recently, ROS have emerged as key players in normal cellular signalling by oxidising redox-sensitive cysteine residues within proteins. Therefore, while high levels of ROS may be harmful and induce oxidative stress, low levels of ROS may actually be beneficial as mediators of redox signalling. In this context, enhancing ROS production in model organisms can extend lifespan, with biological effects dependent on the site, levels, and specific species of ROS. In this review, we examine the role of ROS in ageing, with a particular focus on the importance of the fruit fly Drosophila as a powerful model system to study redox processes in vivo.

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“…The phylogenetic results showed that TcGclc grouped with the Coleoptera. These results suggest that TcGclc has typical conserved features, and could have typical conserved functions in insects, such as scavenging free radicals, 26 age-related changes 27 and ecdysteroid biosynthesis. 16 The temporal expression pattern showed that TcGclc genes were consistently expressed during all developmental stages except the egg stage (Fig.…”

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 86%

The glutathione biosynthesis is involved in metamorphosis, antioxidant function, and insecticide resistance in Tribolium castaneum

Kim,

Gao,

et al. 2024

Pest Management Science

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BACKGROUNDReduced glutathione (GSH) synthesis is vital for redox homeostasis, cell‐cycle regulation and apoptosis, and immune function. The glutamate–cysteine ligase catalytic subunit (Gclc) is the first and rate‐limiting enzyme in GSH synthesis, suggesting the potential use of Gclc as a pesticide target. However, the functional characterization of Gclc, especially its contribution in metamorphosis, antioxidant status and insecticide resistance, is unclear in Tribolium castaneum.RESULTSIn this study, we identified and cloned Gclc from T. castaneum (TcGclc) and found that its expression began to increase significantly from the late larvae (LL) stage (3.491 ± 0.490‐fold). Furthermore, RNA interference‐mediated knockdown of TcGclc resulted in three types of aberration (100% total aberration rate) caused by the downregulation of genes related to the 20‐hydroxyecdysone (20E) pathway. This deficiency was partially rescued by exogenous 20E treatment (53.1% ± 3.2%), but not by antioxidant. Moreover, in the TcGclc knockdown group, GSH content was decreased to 62.3%, and total antioxidant capacity, glutathione peroxidase and total superoxide dismutase activities were reduced by 14.6%, 83.6%, and 82.3%, respectively. In addition, treatment with different insecticides upregulated expression of TcGclc significantly compared with a control group during the late larval stage (P < 0.01).CONCLUSIONOur results indicate that TcGclc has an extensive role in metamorphosis, antioxidant function and insecticide resistance in T. castaneum, thereby expanding our understanding of GSH functions and providing a scientific basis for pest control. © 2024 Society of Chemical Industry.

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The Neuronal Overexpression of Gclc in Drosophila melanogaster Induces Life Extension With Longevity-Associated Transcriptomic Changes in the Thorax

Cited by 9 publications

References 87 publications

Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

Neuroprotective activity of ursodeoxycholic acid in CHMP2B models of frontotemporal dementia

Redox signalling and ageing: insights from Drosophila

The glutathione biosynthesis is involved in metamorphosis, antioxidant function, and insecticide resistance in Tribolium castaneum

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