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Neuron Oct 2023Aging is a complex process involving various systems and behavioral changes. Altered immune regulation, dysbiosis, oxidative stress, and sleep decline are common...
Aging is a complex process involving various systems and behavioral changes. Altered immune regulation, dysbiosis, oxidative stress, and sleep decline are common features of aging, but their interconnection is poorly understood. Using Drosophila, we discover that IM33, a novel immune modulator, and its mammalian homolog, secretory leukocyte protease inhibitor (SLPI), are upregulated in old flies and old mice, respectively. Knockdown of IM33 in glia elevates the gut reactive oxygen species (ROS) level and alters gut microbiota composition, including increased Lactiplantibacillus plantarum abundance, leading to a shortened lifespan. Additionally, dysbiosis induces sleep fragmentation through the activation of insulin-producing cells in the brain, which is mediated by the binding of Lactiplantibacillus plantarum-produced DAP-type peptidoglycan to the peptidoglycan recognition protein LE (PGRP-LE) receptor. Therefore, IM33 plays a role in the glia-microbiota-neuronal axis, connecting neuroinflammation, dysbiosis, and sleep decline during aging. Identifying molecular mediators of these processes could lead to the development of innovative strategies for extending lifespan.
Topics: Animals; Mice; Drosophila; Drosophila Proteins; Dysbiosis; Longevity; Neuroglia; Secretory Leukocyte Peptidase Inhibitor
PubMed: 37582366
DOI: 10.1016/j.neuron.2023.07.010 -
Science (New York, N.Y.) Jul 2023Antimicrobial peptides are host-encoded immune effectors that combat pathogens and shape the microbiome in plants and animals. However, little is known about how the...
Antimicrobial peptides are host-encoded immune effectors that combat pathogens and shape the microbiome in plants and animals. However, little is known about how the host antimicrobial peptide repertoire is adapted to its microbiome. Here, we characterized the function and evolution of the antimicrobial peptide family of Diptera. Using mutations affecting the two () of , we reveal the specific role of for the pathogen and for the gut mutualist . The presence of or like genes across Diptera correlates with the presence of and in their environment. Moreover, and like sequences predict host resistance against infection by these bacteria across the genus . Our study explains the evolutionary logic behind the bursts of rapid evolution of an antimicrobial peptide family and reveals how the host immune repertoire adapts to changing microbial environments.
Topics: Animals; Antimicrobial Peptides; Drosophila melanogaster; Drosophila Proteins; Evolution, Molecular; Microbiota; Host-Pathogen Interactions; Providencia; Acetobacter
PubMed: 37471548
DOI: 10.1126/science.adg5725 -
Nature Neuroscience Apr 2024Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of...
Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.
Topics: Animals; Neuroglia; Drosophila Proteins; Neurons; Drosophila; Homeostasis; Sleep; Lipids
PubMed: 38360946
DOI: 10.1038/s41593-023-01568-1 -
Science (New York, N.Y.) Sep 2023Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum...
Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We show that developmental synapse elimination requires presynaptic Ube3a activity in neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome-associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission. Our findings reveal the physiological role of Ube3a and suggest potential pathogenic mechanisms associated with Ube3a dysregulation.
Topics: Animals; Angelman Syndrome; Autism Spectrum Disorder; Down-Regulation; Drosophila Proteins; Synaptic Transmission; Ubiquitin-Protein Ligases; Drosophila melanogaster; Synapses
PubMed: 37708280
DOI: 10.1126/science.ade8978 -
Science (New York, N.Y.) Feb 2024Insects rely on a family of seven transmembrane proteins called gustatory receptors (GRs) to encode different taste modalities, such as sweet and bitter. We report...
Insects rely on a family of seven transmembrane proteins called gustatory receptors (GRs) to encode different taste modalities, such as sweet and bitter. We report structures of sweet taste receptors GR43a and GR64a in the apo and sugar-bound states. Both GRs form tetrameric sugar-gated cation channels composed of one central pore domain (PD) and four peripheral ligand-binding domains (LBDs). Whereas GR43a is specifically activated by the monosaccharide fructose that binds to a narrow pocket in LBDs, disaccharides sucrose and maltose selectively activate GR64a by binding to a larger and flatter pocket in LBDs. Sugar binding to LBDs induces local conformational changes, which are subsequently transferred to the PD to cause channel opening. Our studies reveal a structural basis for sugar recognition and activation of GRs.
Topics: Animals; Sugars; Taste; Taste Perception; Drosophila melanogaster; Drosophila Proteins; Protein Conformation
PubMed: 38305684
DOI: 10.1126/science.adj2609 -
Development, Growth & Differentiation Aug 2023Cell behavior changes in response to multiple stimuli, such as growth factors, nutrients, and cell density. The mechanistic target of the rapamycin (mTOR) pathway is... (Review)
Review
Cell behavior changes in response to multiple stimuli, such as growth factors, nutrients, and cell density. The mechanistic target of the rapamycin (mTOR) pathway is activated by growth factors and nutrient stimuli to regulate cell growth and autophagy, whereas the Hippo pathway has negative effects on cell proliferation and tissue growth in response to cell density, DNA damage, and hormonal signals. These two signaling pathways must be precisely regulated and integrated for proper cell behavior. This integrative mechanism is not completely understood; nevertheless, recent studies have suggested that components of the mTOR and Hippo pathways interact with each other. Herein, as per contemporary knowledge, we review the molecular mechanisms of the interaction between the mTOR and Hippo pathways in mammals and Drosophila. Moreover, we discuss the advantage of this interaction in terms of tissue growth and nutrient consumption.
Topics: Animals; Protein Serine-Threonine Kinases; Hippo Signaling Pathway; Trans-Activators; Drosophila Proteins; YAP-Signaling Proteins; Nuclear Proteins; TOR Serine-Threonine Kinases; Drosophila; Mammals
PubMed: 37209252
DOI: 10.1111/dgd.12867 -
Science (New York, N.Y.) Nov 2023The global replacement of histones with protamines in sperm chromatin is widespread in animals, including insects, but its actual function remains enigmatic. We show...
The global replacement of histones with protamines in sperm chromatin is widespread in animals, including insects, but its actual function remains enigmatic. We show that in the paternal effect mutant (), sperm chromatin retains germline histones H3 and H4 genome wide without impairing sperm viability. However, after fertilization, sperm chromosomes are targeted by the egg chromosomal passenger complex and engage into a catastrophic premature division in synchrony with female meiosis II. We show that encodes a rapidly evolving transition protein specifically required for the eviction of (H3-H4) tetramers from spermatid DNA after the removal of H2A-H2B dimers. Our study thus reveals an unsuspected role of histone eviction from insect sperm chromatin: safeguarding the integrity of the male pronucleus during female meiosis.
Topics: Animals; Female; Male; Chromatin; Drosophila Proteins; Fertilization; Histones; Spermatozoa; Drosophila melanogaster; Amidine-Lyases; DNA Packaging; Paternal Inheritance
PubMed: 37943933
DOI: 10.1126/science.adh0037 -
ELife Nov 2023Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.
Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.
Topics: Animals; Transcription Factors; Drosophila Proteins; Drosophila melanogaster; Receptors, Notch; Signal Transduction
PubMed: 38018510
DOI: 10.7554/eLife.93706 -
The Journal of Comparative Neurology Oct 2023Insects from high latitudes spend the winter in a state of overwintering diapause, which is characterized by arrested reproduction, reduced food intake and metabolism,...
Insects from high latitudes spend the winter in a state of overwintering diapause, which is characterized by arrested reproduction, reduced food intake and metabolism, and increased life span. The main trigger to enter diapause is the decreasing day length in summer-autumn. It is thus assumed that the circadian clock acts as an internal sensor for measuring photoperiod and orchestrates appropriate seasonal changes in physiology and metabolism through various neurohormones. However, little is known about the neuronal organization of the circadian clock network and the neurosecretory system that controls diapause in high-latitude insects. We addressed this here by mapping the expression of clock proteins and neuropeptides/neurohormones in the high-latitude fly Drosophila littoralis. We found that the principal organization of both systems is similar to that in Drosophila melanogaster, but with some striking differences in neuropeptide expression levels and patterns. The small ventrolateral clock neurons that express pigment-dispersing factor (PDF) and short neuropeptide F (sNPF) and are most important for robust circadian rhythmicity in D. melanogaster virtually lack PDF and sNPF expression in D. littoralis. In contrast, dorsolateral clock neurons that express ion transport peptide in D. melanogaster additionally express allatostatin-C and appear suited to transfer day-length information to the neurosecretory system of D. littoralis. The lateral neurosecretory cells of D. littoralis contain more neuropeptides than D. melanogaster. Among them, the cells that coexpress corazonin, PDF, and diuretic hormone 44 appear most suited to control diapause. Our work sets the stage to investigate the roles of these diverse neuropeptides in regulating insect diapause.
Topics: Animals; Drosophila; Drosophila melanogaster; CLOCK Proteins; Circadian Rhythm; Diapause; Circadian Clocks; Neuropeptides; Drosophila Proteins
PubMed: 37493077
DOI: 10.1002/cne.25522 -
The FEBS Journal Feb 2024Developing tissues are patterned in space and time; this enables them to differentiate their cell types and form complex structures to support different body plans....
Developing tissues are patterned in space and time; this enables them to differentiate their cell types and form complex structures to support different body plans. Although space and time are two independent entities, there are many examples of spatial patterns that originate from temporal ones. The most prominent example is the expression of the genes hunchback, Krüppel, pdm, and castor, which are expressed temporally in the neural stem cells of the Drosophila ventral nerve cord and spatially along the anteroposterior axis of the blastoderm stage embryo. In this Viewpoint, we investigate the relationship between space and time in specific examples of spatial and temporal patterns with the aim of gaining insight into the evolutionary history of patterning.
Topics: Animals; Gene Expression Regulation, Developmental; Drosophila; Drosophila Proteins; Blastoderm; Neural Stem Cells; Body Patterning
PubMed: 37943156
DOI: 10.1111/febs.16995