RESUMO
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.
Assuntos
Metabolismo dos Lipídeos/genética , Neurônios/metabolismo , Doença de Parkinson/genética , alfa-Sinucleína/genética , Animais , Animais Geneticamente Modificados/genética , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Humanos , Gotículas Lipídicas/metabolismo , Lipólise/genética , Proteínas de Membrana Transportadoras/genética , Neuroblastoma/genética , Neurônios/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Perilipina-2/genética , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , ProteóliseRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Arabidopsis/genética , Complexo do Signalossomo COP9/genética , Proteínas Culina/genética , Proteínas de Drosophila/genética , Proteínas Associadas aos Microtúbulos/genética , Animais , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Pontos de Checagem do Ciclo Celular/genética , Divisão Celular/genética , Proliferação de Células/genética , Drosophila/genética , Nicotiana/genética , UbiquitinaRESUMO
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.
Assuntos
Envelhecimento/fisiologia , Coenzima A Ligases/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Proteínas de Transporte de Ácido Graxo/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Retina/metabolismo , Animais , Animais Geneticamente Modificados , Coenzima A Ligases/genética , Proteínas de Drosophila/genética , Metabolismo Energético/fisiologia , Proteínas de Transporte de Ácido Graxo/genética , Gotículas Lipídicas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Retina/citologia , Retina/patologiaRESUMO
Parkinson's disease (PD) is characterized by the progressive accumulation of neuronal intracellular aggregates largely composed of alpha-Synuclein (αSyn) protein. The process of αSyn aggregation is induced during aging and enhanced by environmental stresses, such as the exposure to pesticides. Paraquat (PQ) is an herbicide which has been widely used in agriculture and associated with PD. PQ is known to cause an increased oxidative stress in exposed individuals but the consequences of such stress on αSyn conformation remains poorly understood. To study αSyn pathogenic modifications in response to PQ, we exposed Drosophila expressing human αSyn to a chronic PQ protocol. We first showed that PQ exposure and αSyn expression synergistically induced fly mortality. The exposure to PQ was also associated with increased levels of total and phosphorylated forms of αSyn in the Drosophila brain. Interestingly, PQ increased the detection of soluble αSyn in highly denaturating buffer but did not increase αSyn resistance to proteinase K digestion. These results suggest that PQ induces the accumulation of toxic soluble and misfolded forms of αSyn but that these toxic forms do not form fibrils or aggregates that are detected by the proteinase K assay. Collectively, our results demonstrate that Drosophila can be used to study the effect of PQ or other environmental neurotoxins on αSyn driven pathology.
Assuntos
Drosophila/efeitos dos fármacos , Paraquat/toxicidade , alfa-Sinucleína/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Drosophila/metabolismo , Herbicidas/toxicidade , Masculino , Neurotoxinas/toxicidade , Doença de Parkinson/metabolismoRESUMO
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.
Assuntos
Necrose/genética , Espermatogênese/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Caspase 9/genética , Caspases/genética , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Células Germinativas/crescimento & desenvolvimento , Células Germinativas/patologia , Homeostase/genética , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Masculino , Camundongos , Necrose/patologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismoRESUMO
The unfolded protein response (UPR) is a homeostatic mechanism by which cells regulate levels of misfolded proteins in the endoplasmic reticulum (ER). Although it is well characterized in non-neuronal cells, a proliferation of papers over the past few years has revealed a key role for the UPR in normal neuronal function and as an important driver of neurodegenerative diseases. A complex scenario is emerging in which distinct UPR signalling modules have specific and even opposite effects on neurodegeneration depending on the disease context. Here, we provide an overview of the most recent findings addressing the biological relevance of ER stress in the nervous system.
Assuntos
Retículo Endoplasmático/fisiologia , Homeostase/fisiologia , Doenças Neurodegenerativas/fisiopatologia , Resposta a Proteínas não Dobradas/fisiologia , Animais , Humanos , Estresse Fisiológico/fisiologiaRESUMO
Apoptosis is required during development to eliminate superfluous cells and sculpt tissues; spatial and timed control of apoptosis ensures that the necessary number of cells is eliminated at a precise time in a given tissue. The elimination of supernumerary pigment or inter-ommatidial cells (IOCs) depends on cell-cell communication and is necessary for the formation of the honeycomb-like structure of the Drosophila eye. However, the mechanisms occurring during pupal development and controlling apoptosis of superfluous IOC in space and time remain unclear. Here, we found that split-ends (spen) is required for IOC survival at the time of removal of superfluous IOCs. Loss of spen function leads to abnormal removal of IOCs by apoptosis. We show that spen is required non-autonomously in cone cells for the survival of IOCs by positively regulating the Spitz/EGFR pathway. We propose that Spen is an important survival factor that ensures spatial control of the apoptotic wave that is necessary for the correct patterning and formation of the Drosophila eye.
Assuntos
Apoptose/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila/crescimento & desenvolvimento , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/metabolismo , Células Fotorreceptoras de Invertebrados/fisiologia , Epitélio Pigmentado da Retina/fisiologia , Transdução de Sinais/fisiologia , Animais , Contagem de Células , Drosophila/metabolismo , Fluorescência , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Células Fotorreceptoras de Invertebrados/metabolismo , Células Fotorreceptoras de Invertebrados/ultraestrutura , Pupa/metabolismo , Proteínas de Ligação a RNA , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/ultraestrutura , Estatísticas não ParamétricasRESUMO
Ferritins are protein nanocages that accumulate inside their cavity thousands of oxidized iron atoms bound to oxygen and phosphates. Both characteristic types of eukaryotic ferritin subunits are present in secreted ferritins from insects, but here dimers between Ferritin 1 Heavy Chain Homolog (Fer1HCH) and Ferritin 2 Light Chain Homolog (Fer2LCH) are further stabilized by disulfide-bridge in the 24-subunit complex. We addressed ferritin assembly and iron loading in vivo using novel transgenic strains of Drosophila melanogaster. We concentrated on the intestine, where the ferritin induction process can be controlled experimentally by dietary iron manipulation. We showed that the expression pattern of Fer2LCH-Gal4 lines recapitulated iron-dependent endogenous expression of the ferritin subunits and used these lines to drive expression from UAS-mCherry-Fer2LCH transgenes. We found that the Gal4-mediated induction of mCherry-Fer2LCH subunits was too slow to effectively introduce them into newly formed ferritin complexes. Endogenous Fer2LCH and Fer1HCH assembled and stored excess dietary iron, instead. In contrast, when flies were genetically manipulated to co-express Fer2LCH and mCherry-Fer2LCH simultaneously, both subunits were incorporated with Fer1HCH in iron-loaded ferritin complexes. Our study provides fresh evidence that, in insects, ferritin assembly and iron loading in vivo are tightly regulated.
Assuntos
Drosophila melanogaster/metabolismo , Enterócitos/metabolismo , Ferritinas/metabolismo , Animais , Animais Geneticamente Modificados , Drosophila melanogaster/genética , Ferritinas/química , Ferritinas/genética , Trato Gastrointestinal/metabolismo , Expressão Gênica , Genes Reporter , Genótipo , Ferro/metabolismo , Larva , Modelos Biológicos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Transporte Proteico , Proteínas Recombinantes de FusãoRESUMO
Tight regulation of the visual response is essential for photoreceptor function and survival. Visual response dysregulation often leads to photoreceptor cell degeneration, but the causes of such cell death are not well understood. In this study, we investigated a fatty acid transport protein (fatp) null mutation that caused adult-onset and progressive photoreceptor cell death. Consistent with fatp having a role in the retina, we showed that fatp is expressed in adult photoreceptors and accessory cells and that its re-expression in photoreceptors rescued photoreceptor viability in fatp mutants. The visual response in young fatp-mutant flies was abnormal with elevated electroretinogram amplitudes associated with high levels of Rhodopsin-1 (Rh1). Reducing Rh1 levels in rh1 mutants or depriving flies of vitamin A rescued photoreceptor cell death in fatp mutant flies. Our results indicate that fatp promotes photoreceptor survival by regulating Rh1 abundance.
Assuntos
Drosophila melanogaster , Proteínas de Transporte de Ácido Graxo , Células Fotorreceptoras de Invertebrados , Degeneração Retiniana , Rodopsina , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/fisiologia , Eletrorretinografia , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Expressão Gênica , Mutação , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estimulação Luminosa , Células Fotorreceptoras de Invertebrados/metabolismo , Células Fotorreceptoras de Invertebrados/fisiologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/fisiopatologia , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Rodopsina/genética , Rodopsina/metabolismo , Vitamina D/farmacologiaRESUMO
The canonical role of p53 in preserving genome integrity and limiting carcinogenesis has been well established. In the presence of acute DNA-damage, oncogene deregulation and other forms of cellular stress, p53 orchestrates a myriad of pleiotropic processes to repair cellular damages and maintain homeostasis. Beside these well-studied functions of p53, recent studies in Drosophila have unraveled intriguing roles of Dmp53 in promoting cell division in apoptosis-induced proliferation, enhancing fitness and proliferation of the winner cell in cell competition and coordinating growth at the organ and organismal level in the presence of stress. In this review, we describe these new functions of Dmp53 and discuss their relevance in the context of carcinogenesis.
Assuntos
Apoptose , Proliferação de Células , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Divisão Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
The unfolded protein response (UPR) is a specific cellular process that allows the cell to cope with the overload of unfolded/misfolded proteins in the endoplasmic reticulum (ER). ER stress is commonly associated with degenerative pathologies, but its role in disease progression is still a matter for debate. Here, we found that mutations in the ER-resident chaperone, neither inactivation nor afterpotential A (NinaA), lead to mild ER stress, protecting photoreceptor neurons from various death stimuli in adult Drosophila. In addition, Drosophila S2 cultured cells, when pre-exposed to mild ER stress, are protected from H(2)O(2), cycloheximide- or ultraviolet-induced cell death. We show that a specific ER-mediated signal promotes antioxidant defences and inhibits caspase-dependent cell death. We propose that an immediate consequence of the UPR not only limits the accumulation of misfolded proteins but also protects tissues from harmful exogenous stresses.
Assuntos
Drosophila melanogaster/fisiologia , Retículo Endoplasmático/fisiologia , Degeneração Retiniana/metabolismo , Estresse Fisiológico/fisiologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/citologia , Drosophila melanogaster/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Peróxido de Hidrogênio/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Chaperonas Moleculares/genética , Chaperonas Moleculares/fisiologia , Mutação , Células Fotorreceptoras/citologia , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/metabolismo , Retina/citologia , Retina/efeitos dos fármacos , Retina/metabolismo , Degeneração Retiniana/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Fisiológico/genéticaRESUMO
The growth of an organism and its size determination require the tight regulation of cell proliferation and cell growth. However, the mechanisms and regulatory networks that control and integrate these processes remain poorly understood. Here, we address the biological role of Arabidopsis translationally controlled tumor protein (AtTCTP) and test its shared functions in animals and plants. The data support a role of plant AtTCTP as a positive regulator of mitotic growth by specifically controlling the duration of the cell cycle. We show that, in contrast to animal TCTP, plant AtTCTP is not implicated in regulating postmitotic growth. Consistent with this finding, plant AtTCTP can fully rescue cell proliferation defects in Drosophila loss of function for dTCTP. Furthermore, Drosophila dTCTP is able to fully rescue cell proliferation defects in Arabidopsis tctp knockouts. Our data provide evidence that TCTP function in regulating cell division is part of a conserved growth regulatory pathway shared between plants and animals. The study also suggests that, although the cell division machinery is shared in all multicellular organisms to control growth, cell expansion can be uncoupled from cell division in plants but not in animals.
Assuntos
Arabidopsis/citologia , Arabidopsis/metabolismo , Biomarcadores Tumorais/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Mitose , Animais , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Biomarcadores Tumorais/genética , Proliferação de Células , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disease associated with severe cognitive and motor deficits. BPAN pathophysiology and phenotypic spectrum are still emerging due to the fact that mutations in the WDR45 (WD repeat domain 45) gene, a regulator of macroautophagy/autophagy, were only identified a decade ago. In the first international symposium dedicated to BPAN, which was held in Lyon, France, a panel of international speakers, including several researchers from the autophagy community, presented their work on human patients, cellular and animal models, carrying WDR45 mutations and their homologs. Autophagy researchers found an opportunity to explore the defective function of autophagy mechanisms associated with WDR45 mutations, which underlie neuronal dysfunction and early death. Importantly, BPAN is one of the few human monogenic neurological diseases targeting a regulator of autophagy, which raises the possibility that it is a relevant model to directly assess the roles of autophagy in neurodegeneration and to develop autophagy restorative therapeutic strategies for more common disorders.Abbreviations: ATG: autophagy related; BPAN: beta-propeller protein-associated neurodegeneration; ER: endoplasmic reticulum; KO: knockout; NBIA: neurodegeneration with brain iron accumulation; PtdIns3P: phosphatidylinositol-3-phosphate; ULK1: unc-51 like autophagy activating kinase 1; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting.
Assuntos
Proteínas de Transporte , Doenças Neurodegenerativas , Animais , Humanos , Proteínas de Transporte/genética , Doenças Neurodegenerativas/genética , Autofagia/genética , Mutação , NeurôniosRESUMO
We report a new two-color fluorescent imaging system to visualize the mosaic adult photoreceptor neurons (PRs) in real-time. Using this method, we examined a collection of 434 mutants and identified genes required for PR survival, planar cell polarity (PCP), patterning and differentiation. We could track the progression of PR degeneration in living flies. By introducing the expression of p35, a caspase inhibitor, we found mutations that specifically activate caspase-dependent death. Moreover, we showed that grh is required in R3 for correct PCP establishment. The "Tomato/GFP-FLP/FRT" method allows high-throughput, rapid and precise identification of survival and developmental pathways in living adult PRs at single-cell resolution.
Assuntos
Apoptose , Drosophila/fisiologia , Células Fotorreceptoras de Invertebrados/fisiologia , Animais , Polaridade Celular , Sobrevivência Celular , Proteínas de Ligação a DNA/fisiologia , Proteínas de Drosophila/fisiologia , Fluorescência , Mutação , Fatores de Transcrição/fisiologiaRESUMO
Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy.
Assuntos
Caenorhabditis elegans , Neoplasias , Animais , Apoptose , Morte Celular , Humanos , NecroseRESUMO
Wolbachia is an intracellular bacterium generally described as being a facultative reproductive parasite. However, Wolbachia is necessary for oogenesis completion in the wasp Asobara tabida. This dependence has evolved recently as a result of interference with apoptosis during oogenesis. Through comparative transcriptomics between symbiotic and aposymbiotic individuals, we observed a differential expression of ferritin, which forms a complex involved in iron storage. Iron is an essential element that is in limited supply in the cell. However, it is also a highly toxic precursor of Reactive Oxygen Species (ROS). Ferritin has also been shown to play a key role in host-pathogen interactions. Measuring ferritin by quantitative RT-PCR, we confirmed that ferritin was upregulated in aposymbiotic compared to symbiotic individuals. Manipulating the iron content in the diet, we showed that iron overload markedly affected wasp development and induced apoptotic processes during oogenesis in A. tabida, suggesting that the regulation of iron homeostasis may also be related to the obligate dependence of the wasp. Finally, we demonstrated that iron metabolism is influenced by the presence of Wolbachia not only in the obligate mutualism with A. tabida, but also in facultative parasitism involving Drosophila simulans and in Aedes aegypti cells. In these latter cases, the expression of Wolbachia bacterioferritin was also increased in the presence of iron, showing that Wolbachia responds to the concentration of iron. Our results indicate that Wolbachia may generally interfere with iron metabolism. The high affinity of Wolbachia for iron might be due to physiological requirement of the bacterium, but it could also be what allows the symbiont to persist in the organism by reducing the labile iron concentration, thus protecting the cell from oxidative stress and apoptosis. These findings also reinforce the idea that pathogenic, parasitic and mutualistic intracellular bacteria all use the same molecular mechanisms to survive and replicate within host cells. By impacting the general physiology of the host, the presence of a symbiont may select for host compensatory mechanisms, which extends the possible consequences of persistent endosymbiont on the evolution of their hosts.
Assuntos
Ferritinas/genética , Insetos/genética , Insetos/metabolismo , Ferro/metabolismo , Wolbachia/fisiologia , Aedes/genética , Aedes/crescimento & desenvolvimento , Aedes/metabolismo , Aedes/microbiologia , Animais , Sequência de Bases , Mapeamento Cromossômico , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Drosophila/microbiologia , Feminino , Ferritinas/metabolismo , Regulação da Expressão Gênica , Loci Gênicos , Interações Hospedeiro-Parasita/genética , Insetos/crescimento & desenvolvimento , Insetos/microbiologia , Ferro/farmacologia , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Infecções por Rickettsiaceae/genética , Infecções por Rickettsiaceae/metabolismo , Simbiose/genética , Vespas/genética , Vespas/crescimento & desenvolvimento , Vespas/metabolismo , Vespas/microbiologia , Wolbachia/genéticaRESUMO
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.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Gotículas Lipídicas/química , Neuroglia/citologia , Paraquat/toxicidade , Doença de Parkinson/prevenção & controle , Proteínas de Ligação a RNA/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/metabolismo , Herbicidas/toxicidade , Proteínas de Homeodomínio/genética , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteínas de Ligação a RNA/genéticaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Beta-propeller protein-associated neurodegeneration (BPAN) is caused by mutations in the autophagy gene WDR45/WIPI4. In human, BPAN is associated with static encephalopathy in childhood and neurodegeneration in adulthood (SENDA). It has been proposed that WDR45 mutations cause neurodegeneration due to defective autophagy. Whether these mutations cause a global attenuation or a defect in a subset of autophagy functions is unknown. Based on a recent study showing that wdr45 knockout mice exhibit defective autophagy associated with an increased ER stress, we propose that ER-mediated autophagy, a selective activation of autophagy, is defective in mouse and cellular models of BPAN. We discuss the implication of these findings on the pathophysiological relevance of the relationship between ER stress and autophagy in BPAN as well as other neurodegenerative diseases exhibiting ER stress and defective autophagy.
Assuntos
Autofagia/genética , Proteínas de Transporte/metabolismo , Doenças Neurodegenerativas/metabolismo , Adulto , Animais , Proteínas de Transporte/genética , Criança , Estresse do Retículo Endoplasmático/genética , Humanos , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/genéticaRESUMO
In multicellular organisms, cell death is an essential aspect of life. Over the past decade, the spectrum of different forms of regulated cell death (RCD) has expanded dramatically with relevance in several pathologies such as inflammatory and neurodegenerative diseases. This has been paralleled by the growing awareness of the central importance of autophagy as a stress response that influences decisions of cell life and cell death. Here, we first introduce criteria and methodologies for correct identification of the different RCD forms. We then discuss how the autophagy machinery is directly associated with specific cell death forms and dissect the complex interactions between autophagy and apoptotic and necrotic cell death. This highlights how the balance of the relationship between other cell death pathways and autophagy presides over life and death in specific cellular contexts.