Biology subjects

Venkatachalam, K.

Publications and source records attributed to Venkatachalam, K..

5 recordsLinked to original sources

bioRxiv2025

Neuronal glycolytic reprogramming drives lethality via accelerated aging in a Drosophila model of tauopathy

Neurometabolic dysfunction is a hallmark of Alzheimers disease (AD) and tauopathies. Whether these changes drive pathology or represent compensatory, protective responses remains unresolved. Here, we demonstrate that human tau induces Warburg-like metabolism in Drosophila neurons, characterized by coordinated upregulation of glycolytic enzymes and lactate dehydrogenase that mirrors metabolic signatures in human AD. Despite intact mitochondrial oxidative phosphorylation, tau-expressing fly neurons preferentially utilize glycolysis for ATP production and operate with diminished metabolic reserve. Crucially, this metabolic reprogramming drives rather than protects against pathology as genetic suppression of glycolysis or lactate dehydrogenase completely rescued tau-induced lethality. Further, Gompertz mortality analysis revealed that hyperactive glycolysis in tau neurons drives premature lethality by accelerating biological aging rate without affecting baseline mortality. Collectively, these findings establish aberrant neuronal glycolysis as a cause rather than a consequence of tau pathology, and demonstrate that sustained glycolytic metabolism in mature neurons exacts a specific cost in the form of accelerated aging.

neuroscience↗

bioRxiv2025

In-situ glial cell-surface proteomics identifies pro-longevity factors in Drosophila

Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining healthy brain function. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins in particular is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied a cell-surface proteomic profiling method to glial cells from intact brains in Drosophila, which enabled us to fully profile cell-surface proteomes in-situ, preserving native cell-cell interactions that would otherwise be omitted using traditional proteomics methods. Applying this platform to young and old flies, we investigated how glial cell-surface proteomes change during aging. We identified candidate genes predicted to be involved in brain aging, including several associated with neural development and synapse wiring molecules not previously thought to be particularly active in glia. Through a functional genetic screen, we identified one surface protein, DIP-{beta}, which is down-regulated in old flies and can increase fly lifespan when overexpressed in adult glial cells. We further performed whole-head single-nucleus RNA-seq and revealed that DIP-{beta} overexpression mainly impacts glial and fat cells. We also found that glial DIP-{beta} overexpression was associated with improved cell-cell communication, which may contribute to the observed lifespan extension. Our study is the first to apply in-situ cell-surface proteomics to glial cells in Drosophila, and to identify DIP-{beta} as a potential glial regulator of brain aging.

neuroscience↗

bioRxiv2024

Intracellular Lactate Dynamics Reveal the Metabolic Diversity of Drosophila Glutamatergic Neurons

Rates of lactate production and consumption reflect the metabolic state of many cell types, including neurons. Here, we investigate the effects of nutrient deprivation on lactate dynamics in Drosophila glutamatergic neurons by leveraging the limiting effects of the diffusion barrier surrounding cells in culture. We found that neurons constitutively consume lactate when availability of trehalose, the glucose disaccharide preferred by insects, is limited by the diffusion barrier. Acute mechanical disruption of the barrier reduced this reliance on lactate. Through kinetic modeling and experimental validation, we demonstrate that neuronal lactate consumption rates correlate inversely with their mitochondrial density. Further, we found that lactate levels in neurons exhibited temporal correlations that allowed prediction of cytosolic lactate dynamics after the disruption of the diffusion barrier from pre-perturbation lactate fluctuations. Collectively, our findings reveal the influence of diffusion barriers on neuronal metabolic preferences, and demonstrate the existence of temporal correlations between lactate dynamics under conditions of nutrient deprivation and those evoked by the subsequent restoration of nutrient availability.

neuroscience↗

bioRxiv2021

Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Drosophila model of ALS

Mutations in the gene encoding VAPB (vesicle-associated membrane protein B) cause a familial form of Amyotrophic Lateral Sclerosis (ALS). Expression of an ALS-related variant of vapb (vapbP58S) in Drosophila motor neurons results in morphological changes at the larval neuromuscular junction (NMJ) characterized by the appearance of fewer, but larger, presynaptic boutons. Although diminished microtubule stability is known to underlie these morphological changes, a mechanism for the loss of presynaptic microtubules has been lacking. Here, we demonstrate the suppression of vapbP58S- induced changes in NMJ morphology by either the loss of ER Ca2+ release channels or the inhibition Ca2+/calmodulin (CaM)-activated kinase II (CaMKII). These data suggest a model in which decreased stability of presynaptic microtubules at vapbP58S NMJs result from hyperactivation of CaMKII due to elevated cytosolic [Ca2+]. We attribute the Ca2+ dyshomeostasis to delayed extrusion of cytosolic Ca2+ stemming from a paucity of activity-induced mitochondrial ATP production coupled with elevated rates of ATP consumption. Taken together, our data point to bioenergetic dysfunction as the root cause for the synaptic defects in vapbP58S-expressing Drosophila motor neurons. Significance StatementRates of ATP production and consumption are tightly synchronized in healthy neurons. Whether this synchrony is lost in models of neurodegenerative diseases remains poorly understood. Here, we find that expression of a gene encoding an ALS-causing variant of an ER membrane protein, VAPB, decouples mitochondrial ATP production from neuronal activity. Due to a combination of diminished ATP production and elevated ATP consumption -- established outcomes in ALS neurons -- the levels of ATP in vapbP58S neurons are unable to keep up with the bioenergetic burden of depolarization. The resulting paucity of ATP and attendant decrease in the activity of Ca2+ ATPases results in diminished extrusion of cytosolic Ca2+ in vapbP58S-expressing motor neurons. The accumulation of residual Ca2+ in vapbP58S-expressing neurons underlies paired-pulse facilitation of synaptic vesicle release, and the changes in bouton development at the NMJ. In summary, our findings point to bioenergetic dysfunction due to the loss of activity-induced ATP production as being the cause of the synaptic defects observed in a Drosophila model of ALS.

neuroscience↗

bioRxiv2021

Low doses of the organic insecticide spinosad trigger lysosomal defects, ROS driven lipid dysregulation and neurodegeneration in flies

The plight of insect populations around the world and the threats it poses to agriculture and ecosystems has thrown insecticide use into the spotlight. Spinosad is an organic insecticide, considered less harmful to beneficial insects than synthetic insecticides, but its mode of action remains unclear. Using Drosophila, we show that low doses of spinosad reduce cholinergic response in neurons by antagonizing D6 nAChRs. D6 nAChRs are transported to lysosomes that become enlarged and accumulate upon spinosad treatment. Oxidative stress is initiated in the central nervous system, and spreads to midgut and disturbs lipid storage in metabolic tissues in a D6-dependent manner. Spinosad toxicity was ameliorated with the antioxidant N-Acetylcysteine amide (NACA). Chronic exposures lead to mitochondrial defects, severe neurodegeneration and blindness in adult animals. The many deleterious effects of low doses of this insecticide reported here point to an urgent need for rigorous investigation of its impacts on beneficial insects.

neuroscience↗