In animals, the enzyme pyridox(am)ine 5'-phosphate oxidase (PNPO) is critical for synthesizing the active form of vitamin B6 (VB6), pyridoxal 5'-phosphate (PLP), from inactive vitamers. PLP is a required cofactor for many enzymatic reactions, including the synthesis of GABA and the monoamines. disruption in humans is associated with an array of epilepsy syndromes, while harboring mutations in the sole ortholog, (), display spontaneous seizures and shortened lifespans. These phenotypes are suppressed by PLP dietary supplementation and are exacerbated by restriction of dietary B6 vitamers. In the context of PNPO deficiency, it remains to be resolved what the specific contributions by cellular subpopulations in the nervous system are to the neurological phenotypes. We addressed this question in mutants by expressing human () cDNA in cholinergic, glutamatergic, and GABAergic neurons as well as glia and measuring changes in survival and seizure phenotypes. We found expression in GABAergic neurons largely restored lifespan and attenuated seizure activity, while glial expression also improved phenotypes albeit to a lesser degree. In contrast, expression in either cholinergic or glutamatergic neurons, accounting for most neurons in the fly brain, did not appreciably alter phenotypes. We contrasted these observations with changes in mutants induced by feeding GABA receptor modulators. The GABA agonist SKF-97541 reduced mortality, while GABA or GABA receptor modulators did not improve survival. Together, our data establish a cell-autonomous role for PNPO in GABAergic neurons to support brain function, especially under VB6-restricted conditions.

Behavioral traits are known to evolve rapidly, often even preceding morphological or physiological changes. However, the genomic and neural bases for such rapid behavioral changes remain to be clarified. is a rare example of a species that performs nuptial gift giving, while the mating behaviors of the other two members of the species subgroup, and , remain largely unstudied. In the present study, we characterize and compare mating behaviors of three sibling species of the species subgroup, with the aim of providing a starting point for investigating the neural mechanisms underlying reproductive behavioral divergence in the subgroup. We find that males exhibit a rich repertoire of courtship behaviors-very similar to that of -including tapping, midleg swinging, proboscis extension and nuptial gift giving. In contrast, males perform only tapping and lack the other premating displays, yet they still copulate successfully. We postulate that female promiscuity has promoted the loss of multiple components of the male courtship repertoire in . The relatively recent divergence among these species (∼1.72 Myr between and other two species) suggests that only a few genomic and neural changes underpin the striking differences in mating behavior within the species subgroup. This system offers a promising platform for uncovering the mechanistic basis of rapid behavioral evolution.

Most insects, including agricultural pests and disease vectors, rely on olfaction for key innate behaviors. Consequently, there is growing interest in studying insect olfaction to gain insights into odor-driven behavior and to support efforts in vector control. Calcium imaging using GCaMP fluorescence is widely used to identify olfactory receptor neurons (ORNs) responsive to ethologically relevant odors. However, accurate interpretation of GCaMP signals in the antenna requires understanding both response uniformity within an ORN population and how calcium signals relate to spike activity. To address this, we optimized a dual-modality recording method combining single-sensillum electrophysiology and widefield imaging for ORNs. Calcium imaging showed that homotypic ab2A neurons exhibit similar odor sensitivity, consistent with spike recordings, indicating that a single ORN's response can reliably represent its homotypic counterparts. Furthermore, concurrent dual recordings revealed that peak calcium responses are linearly correlated with spike activity, regardless of imaging site (soma or dendrites), GCaMP variant, odorant, or fly age. These findings validate the use of somatic calcium signals as a reliable proxy for spike activity in fly ORNs and provide a foundation for future large-scale surveys of spike-calcium response relationships across diverse ORN types.

The distinction between normal brain aging and neurodegeneration has traditionally been viewed as a binary classification, yet emerging evidence reveals a complex continuum of shared genetic mechanisms underlying both processes. This review synthesises current understanding of conserved molecular pathways that contribute to age-related neural decline across the spectrum from healthy aging to pathological neurodegeneration. We examine how fundamental cellular processes including protein quality control, mitochondrial dysfunction, inflammation, and synaptic maintenance are genetically regulated and become progressively dysregulated during aging. Key genetic pathways, such as insulin/IGF signalling, autophagy-lysosomal networks, and stress response mechanisms demonstrate remarkable conservation from model organisms to humans, suggesting evolutionary constraints on neural aging processes. The review highlights how genetic variants in these pathways can determine individual trajectories along the aging-neurodegeneration continuum, influencing susceptibility to diseases like Alzheimer's, Parkinson's, and ALS. We discuss evidence from comparative studies in , Drosophila, rodents, and human populations that illuminate shared vulnerability genes and protective factors. Understanding these convergent mechanisms offers unprecedented opportunities for therapeutic intervention, as strategies targeting fundamental aging processes may simultaneously address multiple neurodegenerative conditions. This integrated perspective challenges traditional disease-centric approaches and supports the development of unified therapeutic strategies for promoting healthy brain aging while preventing neurodegeneration.

All metazoan guts harbor commensal communities, from a dozen bacterial species in to hundreds in humans. Here, we condition flies with diets containing varying levels of protein and sugar to investigate the impact of dietary history on the interaction between commensal gut bacteria and feeding adaptation in . We find that appetite increases with dietary protein, dependent on total gut bacteria content, and enhanced by a drug that promotes the growth of short-chain fatty acid (SCFA)-producing gut bacteria. is a potential source of butyrate, while produces acetate. Mono-association with or increases food intake. Mutant strains unable to produce acetate or butyrate have lesser effects. Finally, adding acetate or butyrate to conditioning diets recapitulates the appetitive effect of and , respectively. Our findings suggest that protein-enriched diets enhance appetite by promoting the interaction between commensal bacteria and the host, with bacterial SCFAs as a conduit.

Previous studies have reported associations between risk of Alzheimer's disease (AD) or dementia and rare coding variants in a number of genes. A two-stage strategy was used in which a previously released whole exome sequenced sample was used to prioritise 100 genes showing the strongest evidence for association with AD. These genes were then analysed in a newly released whole genome sequenced sample to identify those which showed statistically significant evidence for rare coding variant association. Association analysis of loss of function (LOF) and nonsynonymous variants was carried out in 18,998 protein-coding genes using 11,188 controls and 5,808 cases, with nonsynonymous variants being annotated using 45 different pathogenicity predictors. The 100 genes showing strongest evidence for association were then analysed in a new sample of 27,749 controls and 13,234 cases using only the pathogenicity predictor which had performed best in the first sample. Four genes were statistically significant after correction for multiple testing: , , and . The association of different categories of variant with AD was characterised and the pattern was seen to vary between genes. This study quantifies the contribution of different types of variant within each gene to AD risk. In general, these variants are probably too rare to be clinically useful for assessing individual risk of AD. Further research into the mechanisms whereby the products of these genes affect AD pathogenesis may aid development of novel therapeutic strategies.

Leigh syndrome spectrum is the most common form of childhood-onset mitochondrial encephalopathy and is characterized by progressive neurodegeneration. Treatment options for this condition remain limited to date. Nonetheless, two lines of research endeavor in the past decade have shown encouraging results worthy of further investigations. First, therapeutic hypoxia appears to improve neurological outcomes, which is somewhat counterintuitive but supported by preclinical evidence. Furthermore, nicotinic acid or nicotinamide riboside could be an adjunctive therapy that enhances the neuroprotective effect of hypoxia. Second, preclinical studies and preliminary clinical experience suggest that sildenafil is potentially disease-modifying for Leigh syndrome. Sildenafil has already been used to treat pulmonary hypertension, and its repurposing for Leigh syndrome has been endorsed by European Medicines Agency. This perspective aims to raise awareness about these progresses, as well as to call for more clinical studies to ensure safe and effective implementation of these treatment approaches in clinical practice.

Males transfer many components in seminal fluid along with sperm during mating. While sex peptide is well established as a key regulator of female reproductive behaviour and success, the roles of other seminal fluid components remain less understood. A new study now reveals functions for a sexually transmitted sugar in providing nutritional value and acting on nutrient-sensing neurons in the brain to maximize reproductive success. Here, we highlight the key findings of this study and explore the potential role of this sugar in male quality assessment by females and in modulation of cryptic female choice.

Pathogenic variants in , a gene encoding for an autophagy adaptor termed ALFY, are linked to neurodevelopmental delay and altered brain size in human probands. While the role of loss-of-function is extensively studied in neurons, little is known about the effects of upregulation in different cell types of the central nervous system (CNS). We show that overexpression of the ortholog, , in either glia or neurons impaired autophagy and locomotion. glial overexpression also increased VNC size and glial nuclei number significantly, whereas neuronal overexpression affected wing and thorax morphology. We identified 79 genes that were differentially expressed and overlapped in flies that overexpress in glial and neuronal cells, respectively. Additionally, upon neuronal overexpression differentially expressed genes clustered in gene ontology categories associated with autophagy and mitochondrial function. Our data indicate that glial as well as neuronal upregulation can have detrimental outcomes on neural function.

Inherited prion diseases (IPD) secondary to mutations of the prion protein gene, exhibit diverse clinical phenotypes, capable of mimicking numerous primary neurodegenerative conditions. We describe the clinical phenotype and neuropathological findings in a family from County Limerick in Ireland presenting with Alzheimer's disease-like cognitive decline and motor symptoms caused by a novel missense mutation of This mutation occurs in the central lysine cluster (CLC; codon 101-110), resulting in substitution of threonine with isoleucine at codon 107 (T107I). This case series highlights that IPD can be hard to distinguish from overlapping clinical syndromes seen in other neurodegenerative diseases. We also discuss similarities and differences of the novel mutation T107I to other pathogenic mutations of the CLC of .

Painful diabetic neuropathy (PDN) is a common complication in patients with type 2 diabetes mellitus (T2DM) with disruption of vitamin D (VD) activity as one of the risk factors. Active VD exerts its biological functions through the vitamin D receptor (VDR), which polymorphisms in the VDR gene can impair. This study aims to establish VDR FokI and ApaI polymorphisms as risk factors for PDN. This case-control study used samples from T2DM patients with and without PDN. Neuropathic pain was diagnosed using the DN4 questionnaire, while FokI and ApaI polymorphisms were examined using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method. Other factors examined included gender, hypertension, current insulin use, obesity, HbA1c levels, and dyslipidemia. A total of 64 subjects were involved in the study. The FokI polymorphism (CT+TT genotype) was a significant risk factor for PDN (OR 4.20; 95% CI [1.47-11.94];  = 0.012). The T allele in the FokI polymorphism significantly increased the risk of PDN by 2.8 times (OR 2.78; 95% CI [1.28-6.01],  = 0.014). The ApaI polymorphism was not significantly associated with PDN. Diabetes duration ≥4.5 years and uncontrolled diabetes were other significant risk factors for PDN. Multivariate analysis identified three significant variables: FokI polymorphism (OR 5.00; 95% CI [1.37-18.24],  = 0.015), insulin use (OR 4.95; 95% CI [1.37-17.87],  = 0.015), and uncontrolled diabetes (OR 3.47; 95% CI [1.03-11.69],  = 0.045). The VDR FokI polymorphism with the T allele is a significant genetic risk factor for PDN in T2DM patients. The VDR ApaI polymorphism was not a significant risk factor for PDN.

The swift updates of public databases and advancements in next-generation sequencing (NGS) technologies have enhanced the genetic identification capacities of epilepsy clinics. This study aimed to evaluate the diagnostic efficacy of NGS in pediatric epilepsy patients as a whole and to present the data obtained in the whole exome sequence analysis. We enrolled 40 children with suspected childhood epilepsy in this study. All patients underwent evaluation by a clinical geneticist or pediatric neurologist and the molecular genetic analysis of those children was performed by whole-exome sequencing (WES). Out of the 40 patients, 12 (30%) received a genetic diagnosis, involving 14 mutations across 13 genes. The cumulative positive diagnostic yield was 30%. Twelve of these patients were identified to have 5 variants previously documented as pathogenic, 9 variants classified as likely pathogenic, and 5 novel variants that have not been reported before. The outcomes indicate that whole-exome sequencing offers great benefits in clinical patient diagnosis, particularly in terms of detecting diagnostic variants. This study underscored the significance of whole exome sequencing (WES) studies, where only a broad gene set is examined in epilepsy patients. This approach has the potential to establish gene-specific phenotypic profiles, particularly by uncovering novel candidate genes in epilepsy patients with well-defined phenotypes. Additionally, conducting validation studies on variants of uncertain clinical significance could enhance the outcome yield.

Forgetting behavior is a common phenomenon that has been widely studied in various model organisms, including (), Drosophila, and mammals such as mice and humans. Understanding the mechanisms underlying forgetting can provide valuable insights into potential treatments for memory-related disorders. In this study, was used as a model organism to establish a forgetting model based on the PA14 pathogen. A proteomic analysis of signaling pathways involved in forgetting revealed the role of the Arp2/3 complex in regulating pathogen-induced forgetting. Manipulation of genes encoding the components of the Arp2/3 complex (, , , , and ) led to a reduction in the duration of pathogen-induced forgetting. Additionally, one hour after pathogen removal, a significant decrease in the mRNA levels of and was observed, along with a reduction in fluorescence in specific tissues of . This study demonstrates that exhibits forgetting behavior towards PA14, with a forgetting duration of approximately 2 hours. Pathogen-induced forgetting is associated with an increase in heterogeneous proteins localized to the cytoskeleton. Moreover, the expression levels of genes related to the Arp2/3 complex (, , , , and ) are reduced, inhibiting cytoskeleton nucleation in cells. This inhibition may contribute to the observed pathogen-induced forgetting in in response to PA14.

Ribonucleoprotein granules (mRNP granules) are thought to contribute to the control of neuronal mRNA translation required for consolidation of long-term memories. Consistent with this, the function of Ataxin-2 in mRNA granule assembly has been shown to be required for long-term olfactory habituation (LTH) in , a form of non-associative memory. Knockdown of Ataxin-2 in either local interneurons (LNs) or projection neurons (PNs) of the insect antennal lobe disrupts LTH while leaving short-term habituation intact, leading to a model in which Ataxin-dependent translational control is required in both presynaptic and postsynaptic elements of the LN-PN synapse, whose potentiation has been causally linked to LTH. Here we use novel and established methods for cell-type specific perturbation to ask: (a) whether Ataxin-2 controls mRNA granule assembly in cell types beyond the few that have been examined; and (b) whether it functions not only in LTH, but also for long-term olfactory associative memory (LTM). We show that Ataxin-2 controls mRNP granule assembly in additional neuronal types, namely Kenyon Cells (KCs) that encode associative memory, as well as more broadly in non-neuronal cells, e.g. in nurse cells in the egg chamber. Furthermore, selective knockdown of Atx2 in α/β and α'/β' KCs blocks appetitive long-term but not short-term associative memories. Taken together these observations support a hypothesis that Ataxin-2 dependent translational control is widely required across different mnemonic circuits for consolidation of respective forms of long-term memories.

Congenital mirror movement disorder refers to involuntary movements on one side of the body that mimic the deliberate movements on the opposite side. Congenital mirror movement is primarily associated with mutations in the DCC netrin-1 receptor (DCC) gene.

Previous studies have reported that rare coding variants in a handful of genes have major effects on risk of Alzheimer's disease (AD). A recent exome wide association study (ExWAS) of dementia in a subset of the UK Biobank cohort implicated a number of genes, including five which were novel. Here we report a similar analysis, carried out on the full cohort of 470,000 exome-sequenced participants. A score was assigned to each participant depending on individual and/or parental diagnosis of dementia. Regression analysis including ε3 and ε4 doses as covariates was applied to gene-wise tests for association with loss of function (LOF) and nonsynonymous variants. 45 tests using different pathogenicity predictors were applied to the first cohort of 200,000 participants. Subsequently the 100 genes showing strongest evidence for association were analysed in the second cohort of 270,000 participants, using only the best-performing predictor for each gene. Three genes achieved statistical significance, , and . The five genes reported as novel in the ExWAS did not produce any appreciable evidence for association in this study. The effects and frequencies of variants in different functional categories were characterised for these genes. Rare coding variants in a small number of genes have important effects on dementia risk. Further study of individual variant effects might elucidate mechanisms of pathogenesis. Incorporating rare variant effects for individual risk assessment might become important if preventative treatments for dementia become available. This research has been conducted using the UK Biobank Resource.

Genes play an important role in the risk of Progressive Supranuclear Palsy (PSP). Some of the major risk genes identified for PSP include , , , and in several ethnic groups. However, the interactions among these genes have not been explored in PSP. Therefore, this prospective case-control study aimed to explore the impact of gene-gene interactions in patients with PSP (n = 106) and healthy subjects (n = 109) of Indian ethnicity. Eight single nucleotide polymorphisms (SNPs) of gene (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, rs7521, rs12185268, and rs62063857, and two SNPs of gene (rs3747957 and rs1411478), one SNP each from (rs1768208) and (rs7571971) genes were genotyped by TaqMan Alleleic Discrimination Assay in all the study participants. Gene-gene interactions among these 12 SNPs were performed using the multi-dimensionality reduction (MDR) test. The combination of SNPs from the gene (rs1467967, rs242557, rs3785883), along with (rs1411478) and (rs1768208), appeared to be the best five-locus model ( < 0.001), suggesting strong interactions among , and genes in modulating the risk of PSP. Strong synergistic interactions were observed within gene (rs1467967, rs244557, rs3785883, rs7521, and rs2471738), and between (rs7521) and (rs1768208). Additionally, moderately strong synergistic interactions were found between (i) (rs1768208) and (rs1411478), and (ii) (rs1768208) and (rs3785883) genes. The findings of this study suggest significant impact of gene-gene interactions amongst , , and genes in modulating the risk of PSP. This implies that epistatic interactions might constitute an important mechanism in delineating the genetic basis of PSP.