Biology subjects

Dus, M.

Publications and source records attributed to Dus, M..

6 recordsLinked to original sources

bioRxiv2025

Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection

Neurons rely on tightly regulated metabolic networks to sustain their high-energy demands, particularly through the coupling of glycolysis and oxidative phosphorylation. Here, we investigate the role of pyruvate kinase (PyK), a key glycolytic enzyme, in maintaining axonal and synaptic integrity in the Drosophila melanogaster neuromuscular system. Using genetic deficiencies in PyK, we show that disrupting glycolysis induces progressive synaptic and axonal degeneration and severe locomotor deficits. These effects require the conserved dual leucine zipper kinase (DLK), Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) Fos transcription factor axonal damage signaling pathway and the SARM1 NADase enzyme, a key driver of axonal degeneration. As both DLK and SARM1 regulate degeneration of injured axons (Wallerian degeneration), we probed the effect of PyK loss on this process. Consistent with the idea that metabolic shifts may influence neuronal resilience in context-dependent ways, we find that pyk knockdown delays Wallerian degeneration following nerve injury, suggesting that reducing glycolytic flux can promote axon survival under stress conditions. This protective effect is partially blocked by DLK knockdown and fully abolished by SARM1 overexpression. Together, our findings help bridge metabolism and neurodegenerative signaling by demonstrating that glycolytic perturbations causally activate stress response pathways that dictate the balance between protection and degeneration depending on the systems state. These results provide a mechanistic framework for understanding metabolic contributions to neurodegeneration and highlight the potential of metabolism as a target for therapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/647282v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1bba464org.highwire.dtl.DTLVardef@25bdd2org.highwire.dtl.DTLVardef@1d12611org.highwire.dtl.DTLVardef@1a3d96_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

dArc1 controls sugar reward valuation in Drosophila melanogaster

The Arc genes -- which include Drosophila Arc1 and Arc2 (dArc) -- evolved from Ty3 retrotransposons and encode proteins that form virus-like capsids. These capsids enable a novel form of intercellular communication by transferring RNAs between cells. However, the specific neuronal circuits and brain processes Arc intercellular signaling regulates remain unknown. Here, we show that loss of both dArc genes in Drosophila melanogaster enhances associative learning in an appetitive conditioning paradigm, where flies associate an odor with sugar rewards. This increased learning performance arises from an increased valuation of sugar rewards: unlike wild-type flies, dArc-/- flies form abnormally strong associations even when the sugar reward is small or has no caloric value. We found that the {gamma}5-dopaminergic neurons of the protocerebral anterior medial (PAM) cluster, which encode the positive valence of sugar rewards, show heightened activity in response to sucrose in dArc-/- flies. We further show that the learning phenotype of dArc-/- flies depends on the formation of capsids, underscoring a direct role for capsid-mediated Arc signaling in sugar valuation. Our findings establish dArc genes as critical regulators of reward valuation in D. melanogaster, acting through a non-cell autonomous mechanism that relies on capsid-mediated communication between cells.

neuroscience↗

bioRxiv2024

HisCl1 regulates gustatory habituation in sweet taste neurons and mediates sugar ingestion in Drosophila

Similar to other animals, the fly, Drosophila melanogaster, reduces its responsiveness to tastants with repeated exposure, a phenomenon called gustatory habituation. Previous studies have focused on the circuit basis of gustatory habituation in the fly chemosensory system 1,2. However, gustatory neurons reduce their firing rate during repeated stimulation 3, suggesting that cell-autonomous mechanisms also contribute to habituation. Here, we used deep learning-based pose estimation and optogenetic stimulation to demonstrate that continuous activation of sweet taste neurons causes gustatory habituation in flies. We conducted a transgenic RNAi screen to identify genes involved in this process and found that knocking down Histamine-gated chloride channel subunit 1 (HisCl1) in the sweet taste neurons significantly reduced gustatory habituation. Anatomical analysis showed that HisCl1 is expressed in the sweet taste neurons of various chemosensory organs. Using single sensilla electrophysiology, we showed that sweet taste neurons reduced their firing rate with prolonged exposure to sucrose. Knocking down HisCl1 in sweet taste neurons suppressed gustatory habituation by reducing the spike frequency adaptation observed in these neurons during high-concentration sucrose stimulation. Finally, we showed that flies lacking HisCl1 in sweet taste neurons increased their consumption of high-concentration sucrose solution at their first meal bout compared to control flies. Together, our results demonstrate that HisCl1 tunes spike frequency adaptation in sweet taste neurons and contributes to gustatory habituation and food intake regulation in flies. Since HisCl1 is highly conserved across many dipteran and hymenopteran species, our findings open a new direction in studying insect gustatory habituation.

neuroscience↗

bioRxiv2022

N6-Adenosine methylation regulates the translation of insulin mRNA

Relatively little is known about the first step of insulin synthesis: the translation of the mRNA. Here we show that the translation of D. melanogaster insulin 2 mRNA (dilp2) is controlled by methylation of N6-adenosine (m6A) in the 3 UTR. Mutations in the m6A writer Mettl3 and methylated-residues in the dilp2 3UTR decreased the levels of dilp2 mRNA associated with the polysomes, and the total amount of dilp2 protein produced. This resulted in aberrant energy homeostasis and diabetic-like phenotypes, consistent with the specific function of dilp2 in adult metabolism. Conserved m6A signatures were also identified in the 3 UTRs of vertebrate insulin mRNAs. These data identify m6A as a key regulator of insulin protein synthesis and energy homeostasis in metazoans and demonstrate an essential role for m6A in translation, with important implications for diabetes and metabolic disease. One-Sentence SummaryThe most abundant modification in eukaryotic mRNAs controls the synthesis of insulin protein in D. melanogaster.

molecular biology↗

bioRxiv2020

The Polycomb Repressive Complex 2.1 Links the Food Environment to a Persistent Neural State

Diets rich in sugar, salt, and fat alter taste perception and food intake, leading to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of D. melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Importantly, half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

neuroscience↗

bioRxiv2019

Dietary sugar inhibits satiation by decreasing the central processing of sweet taste

From humans to flies, exposure to diets rich in sugar and fat lowers taste sensation, changes food choices, and promotes feeding. However, how these peripheral alterations influence eating is unknown. Here we used the genetically tractable organism D. melanogaster to define the neural mechanisms through which this occurs. We characterized a population of protocerebral anterior medial dopaminergic neurons (PAM DANs) that innervates the {beta}2 compartment of the mushroom body and responds to sweet taste. In animals fed a high sugar diet, the response of PAM-{beta}2 to sweet stimuli was reduced and delayed, and sensitive to the strength of the signal transmission out of the sensory neurons. We found that PAM-{beta}2 DANs activity controls feeding rate and satiation: closed-loop optogenetic activation of {beta}2 DANs restored normal eating in animals fed high sucrose. These data argue that diet-dependent alterations in taste weaken satiation by impairing the central processing of sensory signals.

neuroscience↗