Biology subjects

Hodge, J. J. L.

Publications and source records attributed to Hodge, J. J. L..

6 recordsLinked to original sources

bioRxiv2025

Alzheimer's disease risk gene Wwox protects against amyloid pathology through metabolic reprogramming

Genome wide association studies have identified multiple loci that mediate the risk of developing late-onset Alzheimers Disease (LOAD). The gene WW-domain containing oxidoreductase (WWOX) has been identified in recent LOAD risk meta-analyses, yet its function in the brain is poorly understood. Using Drosophila, we discovered that knockdown of the highly conserved Wwox gene impacts longevity and sleep, having roles in both neuronal and glial subtypes. In an amyloid beta 42 (A{beta}42) transgenic model of AD, RNAi-mediated knockdown of Wwox significantly decreased both lifespan and locomotion whilst elevating soluble A{beta}42. Transcriptomic and metabolomic analyses revealed that these effects were accompanied by elevated lactate dehydrogenase (Ldh) mRNA and lactate levels, downstream of an increase in the key unfolded protein response protein Atf4. Strikingly, we found that upregulation of Wwox in the A{beta}42 model through CRISPR activation significantly reduced amyloid load, improved longevity and locomotion. Multi-omics analysis revealed Wwox upregulation partially reversed several key A{beta}42-induced transcriptional pathways in the brain and reduced levels of L-methionine and associated enzymes. These findings support a role for reduced WWOX levels in the genetic risk of developing LOAD via pyruvate metabolism and point towards WWOX activation as a protective therapeutic strategy.

neuroscience↗

bioRxiv2025

Assessing species-specific neonicotinoid toxicity using cross-species chimeric nicotinic acetylcholine receptors in a Drosophila model

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels and the main mediators of synaptic neurotransmission in the insect brain. In insects, nAChRs are pivotal for sensory processing, cognition and motor control, and are the primary target of neonicotinoid insecticides. Neonicotinoids are potent neurotoxins and pollinators such as honey bees are more sensitive and affected by extremely low sub-lethal doses. The pentameric nAChR channel is made up either of five -subunits constituting five ligand-binding sites or a mixture of two to three and {beta} subunits constitute two to three ligand-binding sites. Of particular note, the honey bee nAChR8 subunit is converted into a {beta} subunit (nAChR{beta}2) in Drosophila, raising the question whether this to {beta} conversion makes flies less sensitive to neonicotinoids. To investigate species-specific aspects of neonicotinoid toxicity we CRISPR-Cas9 engineered a cross-species chimeric nAChR subunit by swapping the ligand-binding domain in Drosophila of nAChR{beta}2 with honey bee nAChR8. Toxicity assessment by neonicotinoid thiamethoxam revealed significantly impaired motor functions in climbing and flight assays when comparing the 8/{beta}2 chimeric channel to wild type or a {beta}2 knock-out. However, both the 8/{beta}2 chimeric channel and the {beta}2 knock-out showed the same increased survival after neonicotinoid exposure compared to wild type flies. Combinatorial exposure to neonicotinoids also did not reveal differences. These findings highlight the critical role of nAChR subunit composition in motor control and demonstrate how subtle structural differences can profoundly impact motor function and pesticide response, offering new insights into the molecular mechanisms of neurotoxicity across species.

molecular biology↗

bioRxiv2021

The opposing Chloride Cotransporters KCC and NKCC control locomotor activity inconstant light and during long days.

Cation Chloride Cotransporters (CCCs) regulate intracellular chloride ion concentration ([Cl-]i) within neurons, which can reverse the direction of the neuronal response to the neurotransmitter GABA. Na+ K+ Cl- (NKCC) and K+ Cl- (KCC) cotransporters transport Cl- into or out of the cell, respectively. When NKCC activity dominates, the resulting high [Cl-]i can lead to an excitatory and depolarizing response of the neuron upon GABAA receptor opening, while KCC dominance has the opposite effect. This inhibitory-to-excitatory GABA switch has been linked to seasonal adaption of circadian clock function to changing day length, and its dysregulation is associated with neurodevelopmental disorders such as epilepsy. Constant light normally disrupts circadian clock function and leads to arrhythmic behavior. Here, we demonstrate a function for KCC in regulating Drosophila locomotor activity and GABA responses in circadian clock neurons because alteration of KCC expression in circadian clock neurons elicits rhythmic behavior in constant light. We observed the same effects after downregulation of the Wnk and Fray kinases, which modulate CCC activity in a [Cl-]i-dependent manner. Patch-clamp recordings from clock neurons show that downregulation of KCC results in a more positive GABA reversal potential, while KCC overexpression has the opposite effect. Finally, KCC downregulation represses morning behavioral activity during long photoperiods, while downregulation of NKCC promotes morning activity. In summary, our results support a model in which the regulation of [Cl-]i by a KCC/NKCC/Wnk/Fray feedback loop determines the response of clock neurons to GABA, which is important for adjusting behavioral activity to constant light and long-day conditions.

neuroscience↗

bioRxiv2020

The neonicotinoid insecticide imidacloprid disrupts bumblebee foraging rhythms and sleep

Neonicotinoids have been implicated in the large declines observed in flying insects such as bumblebees, an important group of pollinators[1]. Neonicotinoids are agonists of nicotinic acetylcholine receptors that are found throughout the insect central nervous system, and are the main mediators of synaptic neurotransmission[2]. These receptors are important for the function of the insect central clock and circadian rhythms[3, 4]. The clock allows pollinators to coincide their activity with the availability of floral resources, favourable flight temperatures, as well as impacting learning, navigation and communication[5]. Here we show that exposure to the field relevant concentration of 10 {micro}g/L of imidacloprid can cause a reduction in foraging activity and reduce both locomotor and foraging rhythmicity in Bombus terrestris. Foragers showed an increase in daytime sleep and an increase in the proportion of activity occurring at night. This would likely negatively impact foraging and pollination opportunities, reducing the ability of the colony to grow and reproduce, endangering crop yields.

pharmacology and toxicology↗

bioRxiv2020

Neonicotinoids disrupt memory, circadian behaviour and sleep

Globally, neonicotinoids are still the most used insecticides, despite their well-documented sub-lethal effects on beneficial insects1. Neonicotinoids are agonists at the nicotinic acetylcholine receptors, the main mediator of synaptic transmission in the insect brain2-5, making them highly potent neurotoxins and insecticides6,7. Memory, circadian rhythmicity and sleep are essential for efficient foraging in many pollinating insects, and involve nicotinic acetylcholine receptor signalling2,4,8-10. The effect of field-relevant concentrations of European Union-banned neonicotinoids: imidacloprid, clothianidin and thiamethoxam, as well as the currently unbanned thiacloprid were tested on Drosophila memory, circadian rhythms and sleep. Field-relevant concentrations of imidacloprid, clothianidin and thiamethoxam disrupted learning, behavioural rhythmicity and sleep whilst thiacloprid exposure only affected sleep. Exposure to imidacloprid and clothianidin directly affected neurophysiology, preventing the day/night remodelling and accumulation of pigment dispersing factor neuropeptide in the dorsal terminals of clock neurons. Knockdown of the neonicotinoid susceptible D1 and D{beta}2 nicotinic acetylcholine receptor subunits in the mushroom bodies or clock neurons recapitulated the neonicotinoid like deficits in memory or circadian/sleep behaviour demonstrating that neonicotinoid effects are likely mediated in the mushroom body and clock circuitry. Disruption to learning, circadian rhythmicity and sleep are likely to have far-reaching detrimental effects on beneficial insects in the field.

pharmacology and toxicology↗

bioRxiv2020

A knock-in Drosophila model supports a conserved link between potassium channelopathy and involuntary movement

BackgroundGenetic and in vitro studies have linked a heterozygous gain-of-function mutation (D434G) in the hSlo1 BK (Big potassium) channel to paroxysmal dyskinesia. However, support for this linkage from in vivo models has been lacking. ObjectivesWe aimed to re-create the equivalent mutation to hSlo1 D434G in the fruit fly, Drosophila, and examine how this mutation altered movement and action potential waveforms. MethodsWe generated a knock-in Drosophila model of hSlo1 D434G. We used video-tracking and infra-red beam-break systems to test whether locomotion was altered in this model, and patch-clamp electrophysiology to determine how the mutation affected action potential waveforms. ResultsWe identified profound motor dysfunction and sporadic leg twitches, as well as a reduced width and an enhancement of the afterhyperpolarization phase of action potentials, in the model background. ConclusionOur results support a conserved relationship between enhanced BK channel function and disrupted motor control across distantly related species.

neuroscience↗