Biology subjects

Girard, V.

Publications and source records attributed to Girard, V..

6 recordsLinked to original sources

bioRxiv2026

Lipid droplets accumulate and delay regulated cell death execution

Normal and cancer cells accumulate lipid droplets (LDs) under stress to buffer lipotoxicity, but their role in regulated cell death (RCD) remains incompletely understood. Here, we explored LD accumulation across multiple apoptotic and non-apoptotic RCD modalities in human cancer cells and Drosophila germ cells. We found that LD accumulation arises from de novo LD biogenesis, whereas LD lipolysis remains active--or even enhanced--in dying germ cells and cancer cells, respectively. In Drosophila, LD accumulation in ATGL/Bmm lipase loss of function mutant inhibited germ cell death, supporting a protective role of LDs. Proteomic and imaging analyses revealed a broad redistribution of LD-associated proteins, encompassing lipid metabolism and stress response factors, as well as the pro-apoptotic effector Bax in human cancer cells during cell death. Enhanced LD-mitochondria contacts promoted the translocation of conformationally active Bax from mitochondria to LDs, thereby delaying apoptosis execution. Consistently, LD depletion sensitizes cells to Bax-dependent apoptosis, whereas LD accumulation confers resistance. Collectively, these findings define LD accumulation during cell death as a delaying mechanism in which LDs sequester mitochondrial cell death regulators, attenuating their pro-death activity and revealing potential therapeutic implications for apoptosis-resistant cancers.

cell biology↗

bioRxiv2025

An intercellular metabolic relay for brain sparingin Drosophila

Brain sparing protects growth of the central nervous system (CNS) at the expense of other developing organs during nutrient restriction. This survival strategy is conserved from Drosophila to mammals but little is known about its underlying metabolic mechanisms. Here, we show that CNS uptake and catabolism of circulating glutamine is essential for neural stem cell proliferation during brain sparing but not normal brain development. Glutamine is imported into perineurial glia of the blood-brain-barrier, which upregulate glutaminase (Gls) and vesicular glutamate transporter 1 (VGlut1) to promote glutaminolysis and glutamate secretion. Neural stem cells then import released glutamate via excitatory amino acid transporter 1 (Eaat1) and maintain it at homeostatic levels via glutamine synthetase 1 (Gs1). Glutamine nitrogen contributes surprisingly little to newly synthesized DNA or protein in neural stem cells but its carbon fuels the oxidative tricarboxylic acid cycle. These findings identify an intercellular metabolic relay specifically required to sustain the proliferation of neural stem cells during brain sparing.

developmental biology↗

bioRxiv2024

A Drosophila holidic diet optimised for growthand development

Diets composed of chemically pure components (holidic diets) are useful for determining the metabolic roles of individual nutrients. For the model organism Drosophila melanogaster, existing holidic diets are unable to support rapid growth characteristic of the larval stage. Here, we use a nutrient co-optimisation strategy across more than 50 diet variants to design HoldFast, a holidic medium tailored to fast larval growth and development. We identify dietary amino acid ratios optimal for developmental speed but show that they compromise survival unless vitamins and sterols are co-optimised. Rapid development on HoldFast is not improved by adding fatty acids but it is dependent upon their de novo synthesis in the fat body via fatty acid synthase (FASN). HoldFast outperforms other holidic diets, supporting rates of growth and development close to those of yeast-based diets and, under germ-free conditions, identical. HoldFast provides new opportunities for studying growth and metabolism during Drosophila development.

developmental biology↗

bioRxiv2020

Alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (Syn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between Syn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human Syn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/Midway, fatty acid transport protein/dFatp) and catabolic (lipase Brummer) enzymes, indicating that non-canonical mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by several distinct LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of Syn, which was found at the surface of LDs both in photoreceptors neurons of Drosophila and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of Syn to proteolytic digestion, a phenomenon associated with Syn aggregation in human neurons. We thus propose that Syn cooperates with LD proteins to inhibit lipolysis and that binding of Syn to LDs contributes to the pathogenic misfolding and aggregation of Syn in neurons.

cell biology↗

bioRxiv2020

Split-ends is modulating lipid droplet content in adult Drosophila glial cells and is protective against paraquat toxicity.

Glial cells are early sensors of neuronal injury and are able to store lipids in lipid droplets under oxidative stress conditions. Here, we investigated the glial functions of Spen in the context of Parkinsons disease (PD). Using a data mining approach, we first found that the human ortholog of spen, SPEN/SHARP belongs to the set of astrocyte-expressed genes which mRNA levels are significantly different in the substantia nigra of PD patients as compared to controls. Interestingly, the retrieved list of differentially expressed genes was enriched in genes involved in lipid metabolism. In a Drosophila model of PD, we observed that spen mutant flies were more sensitive to paraquat intoxication. Moreover, the glia-restricted knockdown of spen led to the expansion and the accumulation of lipid droplets as well as the inhibition of Notch pathway. Taken together our results show that Spen regulates lipid metabolism and storage in glial cells and by these means contribute to glia-mediated functions in the context of neurodegeneration.

neuroscience↗

bioRxiv2017

Hydra, a model system for deciphering the mechanisms of aging and resistance to aging

The freshwater cnidarian polyp named Hydra, which can be mass-cultured in the laboratory, is characterized by a highly dynamic homeostasis with a continuous self-renewal of its three adult stem cell populations, the epithelial stem cells from the epidermis, the epithelial stem cells from the gastrodermis, and the multipotent interstitial stem cells, which provide cells of the nervous system, gland cells and germ cells. Two unusual features characterize these stem cells that cannot replace each other, they all avoid G1 to pause in G2, and the two epithelial populations are concomitantly multifunctional and stem cells. H. vulgaris that does not show any signs of aging over the years, resists to weeks of starvation and adapts to the loss of neurogenesis, providing a unique model system to study the resistance to aging. By contrast some strains of a distinct species named H. oligactis undergo a rapid aging process when undergoing gametogenesis or when placed in stress conditions. The aging phenotype is characterized by the rapid loss of somatic interstitial stem cells, the progressive reduction in epithelial stem cell self-renewal, the loss of regeneration, the disorganization of the neuro-muscular system, the loss of the feeding behavior, and the death of all animals within about three months. We review here the possible mechanisms that help H. vulgaris to sustain stem cell self-renewal and thus bypass aging processes. For this, FoxO seems to act as a pleiotropic actor, regulating stem cell proliferation, stress response and apoptosis. In H. oligactis, the regulation of the autophagy flux differs between aging-sensitive and aging-resistant animals, pointing to a key role for proteostasis in the maintenance of a large pool of active and plastic epithelial stem cells.

evolutionary biology↗