RESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αSyn) 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 αSyn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human αSyn 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 (brummer TG lipase) enzymes, indicating that alternative mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, which localized to LDs in both Drosophila photoreceptor neurons and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of αSyn to proteolytic digestion, a characteristic of αSyn aggregation in human neurons. We propose that αSyn cooperates with LD proteins to inhibit lipolysis and that binding of αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn in neurons.
Asunto(s)
Metabolismo de los Lípidos/genética , Neuronas/metabolismo , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Animales , Animales Modificados Genéticamente/genética , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Humanos , Gotas Lipídicas/metabolismo , Lipólisis/genética , Proteínas de Transporte de Membrana/genética , Neuroblastoma/genética , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Perilipina-2/genética , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , ProteolisisRESUMEN
Translationally Controlled Tumor Protein (TCTP) controls growth by regulating the G1/S transition during cell cycle progression. Our genetic interaction studies show that TCTP fulfills this role by interacting with CSN4, a subunit of the COP9 Signalosome complex, known to influence CULLIN-RING ubiquitin ligases activity by controlling CULLIN (CUL) neddylation status. In agreement with these data, downregulation of CSN4 in Arabidopsis and in tobacco cells leads to delayed G1/S transition comparable to that observed when TCTP is downregulated. Loss-of-function of AtTCTP leads to increased fraction of deneddylated CUL1, suggesting that AtTCTP interferes negatively with COP9 function. Similar defects in cell proliferation and CUL1 neddylation status were observed in Drosophila knockdown for dCSN4 or dTCTP, respectively, demonstrating a conserved mechanism between plants and animals. Together, our data show that CSN4 is the missing factor linking TCTP to the control of cell cycle progression and cell proliferation during organ development and open perspectives towards understanding TCTP's role in organ development and disorders associated with TCTP miss-expression.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Arabidopsis/genética , Complejo del Señalosoma COP9/genética , Proteínas Cullin/genética , Proteínas de Drosophila/genética , Proteínas Asociadas a Microtúbulos/genética , Animales , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Puntos de Control del Ciclo Celular/genética , División Celular/genética , Proliferación Celular/genética , Drosophila/genética , Nicotiana/genética , UbiquitinaRESUMEN
Increasing evidence suggests that dysregulation of lipid metabolism is associated with neurodegeneration in retinal diseases such as age-related macular degeneration and in brain disorders such as Alzheimer's and Parkinson's diseases. Lipid storage organelles (lipid droplets, LDs), accumulate in many cell types in response to stress, and it is now clear that LDs function not only as lipid stores but also as dynamic regulators of the stress response. However, whether these LDs are always protective or can also be deleterious to the cell is unknown. Here, we investigated the consequences of LD accumulation on retinal cell homeostasis under physiological and stress conditions in Drosophila and in mice. In wild-type Drosophila, we show that dFatp is required and sufficient for expansion of LD size in retinal pigment cells (RPCs) and that LDs in RPCs are required for photoreceptor survival during aging. Similarly, in mice, LD accumulation induced by RPC-specific expression of human FATP1 was non-toxic and promoted mitochondrial energy metabolism in RPCs and non-autonomously in photoreceptor cells. In contrast, the inhibition of LD accumulation by dFatp knockdown suppressed neurodegeneration in Aats-metFB Drosophila mutants, which carry elevated levels of reactive oxygen species (ROS). This suggests that abnormal turnover of LD may be toxic for photoreceptors cells of the retina under oxidative stress. Collectively, these findings indicate that FATP-mediated LD formation in RPCs promotes RPC and neuronal homeostasis under physiological conditions but could be deleterious for the photoreceptors under pathological conditions.
Asunto(s)
Envejecimiento/fisiología , Coenzima A Ligasas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/fisiología , Proteínas de Transporte de Ácidos Grasos/metabolismo , Gotas Lipídicas/metabolismo , Metabolismo de los Lípidos/fisiología , Retina/metabolismo , Animales , Animales Modificados Genéticamente , Coenzima A Ligasas/genética , Proteínas de Drosophila/genética , Metabolismo Energético/fisiología , Proteínas de Transporte de Ácidos Grasos/genética , Gotas Lipídicas/patología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/patología , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Retina/citología , Retina/patologíaRESUMEN
The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis.
Asunto(s)
Necrosis/genética , Espermatogénesis/genética , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis/genética , Caspasa 9/genética , Caspasas/genética , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Células Germinativas/crecimiento & desarrollo , Células Germinativas/patología , Homeostasis/genética , Humanos , Hiperplasia/genética , Hiperplasia/patología , Masculino , Ratones , Necrosis/patología , Testículo/crecimiento & desarrollo , Testículo/metabolismoRESUMEN
In recent years, concerns about the harmful effects of synthetic UV filters on the environment have highlighted the need for natural sun blockers. Lignin, the most abundant aromatic renewable biopolymer on Earth, is a promising candidate for next-generation sunscreen due to its inherent UV absorbance and its green, biodegradable, and biocompatible properties. Lignin's limitations, such as its dark color and poor dispersity, can be overcome by reducing particle size to the nanoscale, enhancing UV protection and formulation. In this study, 100-200 nm lignin nanoparticles (LNPs) were prepared from various biomass by-products (hardwood, softwood, and herbaceous material) using an eco-friendly anti-solvent precipitation method. Pure lignin macroparticles (LMPs) were extracted from beech, spruce, and wheat straw using an ethanol-organosolv treatment and compared with sulfur-rich kraft lignin (KL). Sunscreen lotions made from these LMPs and LNPs at various concentrations demonstrated novel UV-shielding properties based on biomass source and particle size. The results showed that transitioning from the macro- to nanoscale increased the sun protection factor (SPF) by at least 2.5 times, with the best results improving the SPF from 7.5 to 42 for wheat straw LMPs and LNPs at 5 wt%. This study underscores lignin's potential in developing high-quality green sunscreens, aligning with green chemistry principles.
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This article presents new research on producing lignin nanoparticles (LNPs) using the antisolvent nanoprecipitation method. Acetone (90%) served as the lignin solvent and water (100%) as the antisolvent, using five types of lignins from various sources. Comprehensive characterization techniques, including NMR, GPC, FTIR, TEM, and DLS, were employed to assess both lignin and LNP properties. The antioxidant activity of the LNPs was evaluated as well. The results demonstrated the successful formation of spherical nanoparticles below 100 nm with initial lignin concentrations of 1 and 2%w/v. The study highlighted the crucial role of lignin purity in LNP formation and colloidal stability, noting that residual carbohydrates adversely affect efficiency. This method offers a straightforward, environmentally friendly approach using cost-effective solvents, applicable to diverse lignin sources. The innovation of this study lies in its demonstration of a cost-effective and eco-friendly method to produce stable, nanometric-sized spherical LNPs. These LNPs have significant potential as reinforcement materials due to their reinforcing capability, hydrophilicity, and UV absorption. This work underscores the importance of starting material purity for optimizing the process and achieving the desired nanometric dimensions, marking a pioneering advancement in lignin-based nanomaterials.
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Lipid droplets are highly dynamic intracellular organelles that store neutral lipids such as cholesteryl esters and triacylglycerols. They have recently emerged as key stress response components in many different cell types. Lipid droplets in the nervous system are mostly observed in vivo in glia, ependymal cells and microglia. They tend to become more numerous in these cell types and can also form in neurons as a consequence of ageing or stresses involving redox imbalance and lipotoxicity. Abundant lipid droplets are also a characteristic feature of several neurodegenerative diseases. In this minireview, we take a cell-type perspective on recent advances in our understanding of lipid droplet metabolism in glia, neurons and neural stem cells during health and disease. We highlight that a given lipid droplet subfunction, such as triacylglycerol lipolysis, can be physiologically beneficial or harmful to the functions of the nervous system depending upon cellular context. The mechanistic understanding of context-dependent lipid droplet functions in the nervous system is progressing apace, aided by new technologies for probing the lipid droplet proteome and lipidome with single-cell type precision.
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Vector mosquitoes contribute significantly to the global burden of diseases in humans, livestock and wildlife. As such, the spatial distribution and abundance of mosquito species and their surveillance cannot be ignored. Here, we surveyed mosquito species across major tourism hotspots in semi-arid Botswana, including, for the first time, the Central Kalahari Game Reserve. Our results reported several mosquito species across seven genera, belonging to Aedes, Anopheles, Culex, Mansonia, Mimomyia, Coquillettidia and Uranotaenia. These results document a significant species inventory that may inform early warning vector-borne disease control systems and likely help manage the risk of emerging and re-emerging mosquito-borne infections.
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Glial cells are early sensors of neuronal injury and can store lipids in lipid droplets under oxidative stress conditions. Here, we investigated the functions of the RNA-binding protein, SPEN/SHARP, in the context of Parkinson's disease (PD). Using a data-mining approach, we found that SPEN/SHARP is one of many astrocyte-expressed genes that are significantly differentially expressed in the substantia nigra of PD patients compared with control subjects. Interestingly, the differentially expressed genes are enriched in lipid metabolism-associated genes. In a Drosophila model of PD, we observed that flies carrying a loss-of-function allele of the ortholog split-ends (spen) or with glial cell-specific, but not neuronal-specific, spen knockdown were more sensitive to paraquat intoxication, indicating a protective role for Spen in glial cells. We also found that Spen is a positive regulator of Notch signaling in adult Drosophila glial cells. Moreover, Spen was required to limit abnormal accumulation of lipid droplets in glial cells in a manner independent of its regulation of Notch signaling. Taken together, our results demonstrate that Spen regulates lipid metabolism and storage in glial cells and contributes to glial cell-mediated neuroprotection.