The muscle of Lawrence (MOL) is a pair of male-specific longitudinal muscles located below the tergite of the fifth abdominal segment in adult Drosophila melanogaster. For the MOL to form, the innervating motor neuron (MOL-inducing neuron: Mind neuron) must express male-specific products of the fruitless (fru) gene, collectively called FruM. We localized a cis-regulatory element of the fru gene that promotes its expression in the Mind neuron to a short genomic interval lying between -4.3 and -5.7 kb upstream of the distal promotor P1 of the fru gene. Comparisons of the sequences of this genomic interval between D. melanogaster, which carries a single MOL pair and D. subobscura, a distant relative that carries two MOL pairs, revealed five conserved stretches, Boxes A-E, tandemly aligned in a single copy (D. melanogaster) or in duplicate (D. subobscura). The Gal4 transgenes carrying Boxes A, B, and E together were able to induce the MOL when used to drive UAS-fruM. Deleting Boxes A, B and E from the genome resulted in loss of the MOL, with occasional formation of vestigial MOL-like muscles. Conversely, reintroducing Boxes A, B, and E into the deletant restored the MOL. We conclude that Boxes A, B, and E comprise a major element that promotes fru expression in the Mind neuron for MOL induction, and we propose to call it the cis-element for MOL induction (ceMOi).
Developmental and epileptic encephalopathies (DEEs) are severe early-onset disorders featuring refractory seizures, abnormal EEGs, and developmental delays. Clinically and etiologically heterogeneous, they include subtypes such as Dravet syndrome and EIMFS. An increasing number are recognized as etiology-specific, with distinct genetic causes corresponding to characteristic phenotypes, highlighting the need for thorough diagnostic evaluation. This study utilized a multidisciplinary diagnostic approach to investigate DEE. In this descriptive case series, the reported novel variants include a PLPBP duplication (c.596dup), an SCN1A insertion (c.3879dup), and an SLC6A1 in-frame deletion (c.943_945del). Bioinformatics and segregation analysis supported their pathogenicity, with each variant linked to a distinct clinical phenotype. The reported novel variants broaden the phenotypic and genotypic spectrum of these disorders and inform clinical management and genetic counseling.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor dysfunctions. Although the underlying mechanisms are multifactorial, oxidative stress, inflammation, and dopaminergic deficits are central to its pathogenesis. D-Ribose-L-Cysteine (DRLC), a glutathione (GSH) precursor, has shown potential protective effects in models of human diseases. This study investigates the neuroprotective effects of DRLC against rotenone (ROT)-induced PD-like pathology in Drosophila melanogaster. Adult Drosophila (Harwich strain) were segregated into five groups and administered either a control diet, 500 μM ROT, or ROT in conjunction with DRLC (125, 250, or 500 μM) for a duration of 14 days. Longevity, locomotor, and olfactory assays were performed. Biochemical analysis of dissected fly brains assessed redox status markers, pro-inflammatory cytokines, apoptosis indicators, neurotransmitter levels, and dopa-decarboxylase (DDC) gene expression. ROT exposure reduced survival by 25%, significantly impaired motor and olfactory functions, increased reactive oxygen species (ROS) levels, disrupted neurotransmission, elevated TNF-α and caspase-3 levels, and downregulated DDC gene expression. DRLC co-treatment improved survival and motor performance in a dose-dependent manner while also decreasing ROS, TNF-α, and caspase-3 expression. DRLC restored dopamine and acetylcholine levels and GSH concentrations compared to the ROT-only group. DRLC also upregulated DDC gene expression. In conclusion, DRLC mitigates ROT-induced PD-like neurotoxicity in Drosophila through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, possibly via enhanced GSH synthesis and dopamine regulation. Although we cannot fully rule out the possibility that DRLC affected rotenone ingestion or feeding behavior, the fact that ROT-dependent phenotypes persisted in the absence of DRLC and were only selectively reversed by DRLC suggests a neuroprotective effect.
Hereditary spastic paraplegia (HSP) encompasses a clinically and genetically heterogeneous group of neurodegenerative disorders, characterized by progressive lower limb spasticity due to corticospinal tract degeneration. While traditionally regarded as monogenic, recent genomic advances have revealed more complex inheritance models, including oligogenic and polygenic contributions. This mini-review examines the evolving genetic landscape of HSP, integrating established monogenic forms with emerging evidence of cumulative variant burden. Importantly, current evidence remains insufficient to establish oligogenic inheritance as a validated or broadly applicable pathogenic mechanism in HSP, and most available data should be considered exploratory and hypothesis-generating rather than conclusive. Monogenic subtypes such as SPG4, SPG7, and SPG11 remain central to current understanding, but analyses of large sequencing cohorts show that up to 40% of cases lack a single-gene explanation. Both statistical analyses and illustrative reports, such as ultra-rare variant enrichment involving SYNE1, CAPN1, and PGAP1, suggest that oligogenic inheritance may operate in a subset of unresolved cases, although current evidence remains preliminary and not yet broadly validated. Pathogenic mechanisms converge on shared molecular pathways including microtubule dynamics, endoplasmic reticulum shaping, lipid metabolism, mitochondrial maintenance, and vesicular trafficking. Recognition of these multilayered mechanisms informs diagnostic strategies, favoring whole-exome or genome sequencing, variant burden analysis, and refined genetic counselling. Functional studies in cellular and animal models, coupled with biomarker discovery, are crucial to unravel gene-gene interactions and identify therapeutic targets. HSP exemplifies a genetic continuum ranging from high-penetrance monogenic forms to genetically unresolved phenocopies and putative oligogenic cases influenced by cumulative variant burden. Accordingly, diagnosis should incorporate multi-locus models as a hypothesis-testing framework in selected unresolved cases rather than as an established default explanation, counselling must address probabilistic inheritance, and therapeutic development should prioritize pathway-based interventions. Multidisciplinary integration of genomic, mechanistic, and clinical insights is essential to achieve precise diagnoses and personalized therapies.
Sulfate is a vital nutrient for healthy brain development. More than 90 sulfate-related genes are highly conserved across mammalian species, with 16 of these genes being clinically reportable for adverse brain conditions. To determine the potential involvement of additional sulfate-related genes in human neuropathology, this study curated the spatial and temporal expression patterns of all known sulfate biology genes in the human fetal brain from 8 to 37 post conception weeks (pcw) using data from the BrainSpan database and performed network analysis to cluster sulfate-related genes with genes involved in neurodevelopmental processes. A total of 64 sulfate-related genes were abundantly or moderately expressed in 11 brain regions throughout gestation. Steady state expression was observed for some of these genes from 8 to 37 pcw, including genes that encode sulfotransferases (CHST12, CHST7), sulfatases (ARSA, SULF2, TPST1, TPST2), sulfatase modifying enzyme (SUMF2), key enzymes in amino acid metabolism (CDO1, CTH), sulfate transporter (SLC26A11), as well as genes involved in neurodevelopmental processes (ACTG1, TUBA1A, MAPT, UBE3A, DCHS1, WWOX). Between 21-24 weeks, there were numerous clusters of sulfate biology genes with neurodevelopmental genes involved in neuronal migration (FAT4) and synaptogenesis (CBLN2, WNT4, MAPT, FOXP2). At 8-13 and 17-21 pcw, fifteen sulfate genes (ARSF, CHST1, CHST2, CHST13, GAL3ST3, GOT1, IDS, HS3ST2, HS3ST4, HS6ST3, SLC26A8, STS, SULT1A1, SULT4A1, UST) were expressed in the hippocampus and clustered with genes involved in neurogenesis, differentiation and synaptogenesis (MAPT, DNER, NEUROD1). Overall, this study identified 48 sulfate-related genes with moderate/abundant expression in the fetal brain that are coexpressed with genes for neurodevelopmental processes but are not considered in clinical settings. These findings provide information for future studies into the physiological roles of sulfate-related genes that are expressed in the fetal brain.
Previous studies indicate a link between an exceptionally long GA-repeat in the Zinc finger MYM-type containing 3 (ZMYM3) gene and higher-order brain functions, reflected in human-specific cognitive disorders. Here, we studied this GA-repeat in a cohort of unrelated male subjects, consisting of patients affected by autism spectrum disorder (ASD) (n = 100) and controls (n = 200). We also analyzed pooled samples from this study and previous studies of this GA-repeat in three other major psychiatric disorders (n = 721), including schizophrenia (SCZ), bipolar disorder (BD), and late-onset neurocognitive disorder (NCD) and pooled controls (n = 487). An allele at the extreme short end (17-repeat) was detected in the ASD cases, which was not detected in the control samples (mid-p ≤ 0.05). This allele overlapped with the extreme allele detected in SCZ, BD, and late-onset NCD. Furthermore, we found a significantly different genetic architecture at this locus in the ASD patients vs. pooled controls. In conclusion, we report a significant association between the human ZMYM3 17-repeat allele and ASD, which overlaps with SCZ, BD, and late-onset NCD. Our findings reinforce the hypothesis that low-frequency alleles at the extreme allele lengths at this locus co-occur with a number of major psychiatric disorders and undergo natural selection.
Overlapping neuropsychiatric and cardiac features in rare monogenic syndromes stem from shared gene expression. Pathogenic gain-of-function RYR2 variants, leading to a lethal cardiac arrhythmia syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT), have also been associated with neuropsychiatric disorders such as epilepsy, schizophrenia, and intellectual disability. Neuropsychiatric phenotypes have not been reported in patients with calcium release deficiency syndrome (CRDS), a recently described inherited arrhythmia disorder distinct from CPVT caused by loss-of-function RYR2 variants. Whether there is a robust association between ultra-rare RYR2 variants and neuropsychiatric phenotypes in large population databases and disease cohorts has not been determined to-date. Here, we explore the association of RYR2 variants with neuropsychiatric disorders in 748,879 individuals from multiple biobanks, including 155,236 non-Europeans, and in neuropsychiatric disease cohorts. Our analyses suggest an association between RYR2 variants and epilepsy, while links with other disorders were not robust. In this process, a previously uncharacterized RYR2 variant (p.Y4962N) with conflicting reported pathogenicity was found to be associated with both cardiac and neuropsychiatric phenotypes. To better understand the potential impact of the variant, we further assessed its mechanistic impact and found that RyR2-p.Y4962N results in loss-of-function. Such a finding has not been reported previously in association with RYR2 loss-of-function variants or CRDS. Altogether, our study expands our understanding of the involvement of RYR2 variants in neurocardiac phenotypes in general populations and disease cohorts, which could enhance personalized medicine efforts by integrating cardiac and neuropsychiatric risk profiles.
E-cigarettes also known as vape, are rapidly gaining recognition as having potential neurological consequences, yet their neural effects on sensory valence and associative learning remain poorly understood, necessitating urgent investigation into their potential neurocognitive effects. This is particularly important because nicotine, the primary psychoactive component in most vape liquid, acts directly on nicotinic acetylcholine receptors (nAChRs) in the brain. Hence, the role of nAChRs in the control of neural learning and memory in response to this drug is fundamental. Here, we investigated how vape exposure modulates olfactory behaviour, reinforcement processing, and the influence α7 or β2 nicotinic acetylcholine receptors (nAChR) mutation in Drosophila melanogaster. In this study, vape exposure significantly affected motor performance and cholinergic function, as evidenced by altered negative geotaxis and acetylcholinesterase (AChE) activity after chronic treatment with 0.06, 0.08, and 0.12 mg/mL vape in different flies genotypes. Addionally, using a combination of innate odour preference and conditioning assays, we found that wild-type flies displayed an inherent attraction to strawberry odour and avoidance of aversive one (marula). However, exposure to vape altered these intrinsic preferences, reversing attraction to aversion and attenuating innate avoidance exhibited as "addiction-like" behaviour in wild-type flies. Notably, these vape-induced shifts in odour valence were abolished in nAChRα7-/- and nAChRβ2-/- mutants, implicating nicotinic acetylcholine receptor signaling in mediating nicotine's neuromodulatory effects. However, α7 and β2 significantly differ in odour discrimination and detection of chemically related odour pairs, while β2 nAChR mutants display a strong resistance to learning, further impairing memory performance. Together, our findings indicate that vape acts not merely as an associative cue but as a neuromodulator that reshapes innate sensory valence through α7 and β2-containing nAChRs. This work establishes Drosophila as a powerful genetic model for understanding the neural mechanisms by which vape exposure alters odour valence and reinforcement processing, providing new insight into the addictive properties of vaping.
Calcium (Ca2+) homeostasis is fundamental to neuronal physiology, including in the regulation of membrane excitability and synaptic transmission. Disruptions in the ion transporters regulating Ca2+ influx and efflux are clearly linked to seizure disorders and age-related neurodegenerative disease. Yet, the specific contributions of variants in genes encoding these transporters to neurological disease remain to be fully understood. Drosophila melanogaster has proven to be a powerful genetic model for uncovering such mechanisms, particularly through studies of mutants that display temperature-sensitive (TS) behavioral phenotypes. In a forward genetic screen, we identified a mutant line that exhibited TS convulsions along with progressive, age-dependent neurodegeneration. We mapped the mutation to Nckx30c, specifically within the transmembrane ion-binding region of this K+-dependent Na+/Ca2+ exchanger. Characterization of this mutant, together with a second Nckx30c allele, revealed TS convulsions, impaired locomotion, a markedly shortened lifespan, neurodegeneration with age, along with structural defects at larval and adult neuromuscular junctions (NMJs). Nckx30c mutants also displayed altered neural motor circuit performance. Gene expression analysis confirmed that Nckx30c levels were reduced in heads of Nckx30c loss-of-function mutants. Tissue-specific manipulation revealed that knockdown of Nckx30c in neurons recapitulated the TS convulsions, locomotor defects, and shortened lifespan phenotypes. Drosophila Nckx30c is highly conserved and shares homology with mammalian SLC24A2, a solute carrier family 24 member whose neurological role is not yet fully elucidated. Our work establishes Nckx30c as an essential regulator of neuronal health and provides an in vivo framework for investigating the contribution of SLC24A2 to neuronal Ca2+ homeostasis, seizures and age-related neurodegeneration.
Long non-coding RNA XIST (LncRNA XIST) and microRNA-133b (miR-133b) have been implicated in Parkinson's disease (PD)-related pathophysiology and may serve as potential circulating biomarkers. The aim of this study was to study the serum expression levels of LncRNA XIST and miR-133b in PD patients and healthy controls, assess their correlation with disease severity, and evaluate their diagnostic value. Peripheral blood was obtained from 63 patients with PD and 21 healthy controls. Serum RNA was extracted, and the expression of LncRNA XIST and miR-133b was measured. PD severity was determined through standardized neurological evaluation, incorporating the Unified Parkinson's Disease Rating Scale (UPDRS) for symptom burden and the Hoehn and Yahr (H&Y) scale for disease staging. Serum LncRNA XIST levels were significantly higher in PD patients compared with controls, whereas miR-133b levels were significantly lower. LncRNA XIST positively correlated with UPDRS total score (r = .279, p = .027) and H&Y stage (r = .926, p < .001), while miR-133b showed a strong negative correlation with H&Y stage (r = -.957, p < .001). Receiver operating characteristic analysis revealed that LncRNA XIST had an area under the curve (AUC) of 0.824, miR-133b had an AUC of 0.787, and the combined model yielded an AUC of 0.807. The combined model performed better than miR-133b alone but slightly lower than LncRNA XIST alone. Serum LncRNA XIST and miR-133b are significantly altered in PD and strongly associated with disease stage. Both biomarkers demonstrate good diagnostic performance, and their combined use may provide complementary information for PD diagnosis and monitoring.
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. PNPO disruption in humans is associated with an array of epilepsy syndromes, while Drosophila harboring mutations in the sole PNPO ortholog, sugarlethal (sgll), 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 sgll mutants by expressing human PNPO (hPNPO) cDNA in cholinergic, glutamatergic, and GABAergic neurons as well as glia and measuring changes in survival and seizure phenotypes. We found hPNPO expression in GABAergic neurons largely restored lifespan and attenuated seizure activity, while glial expression also improved sgll phenotypes albeit to a lesser degree. In contrast, hPNPO expression in either cholinergic or glutamatergic neurons, accounting for most neurons in the fly brain, did not appreciably alter sgll phenotypes. We contrasted these observations with changes in sgll mutants induced by feeding GABA receptor modulators. The GABAB agonist SKF-97541 reduced mortality, while GABA or GABAA 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. Drosophila subobscura is a rare example of a species that performs nuptial gift giving, while the mating behaviors of the other two members of the subobscura species subgroup, D. madeirensis and D. guanche, remain largely unstudied. In the present study, we characterize and compare mating behaviors of three sibling species of the subobscura species subgroup, with the aim of providing a starting point for investigating the neural mechanisms underlying reproductive behavioral divergence in the subobscura subgroup. We find that D. madeirensis males exhibit a rich repertoire of courtship behaviors-very similar to that of D. suboscura-including tapping, midleg swinging, proboscis extension and nuptial gift giving. In contrast, D. guanche 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 D. guanche. The relatively recent divergence among these species (∼1.72 Myr between D. guanche and other two species) suggests that only a few genomic and neural changes underpin the striking differences in mating behavior within the subobscura species subgroup. This system offers a promising platform for uncovering the mechanistic basis of rapid behavioral evolution.
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 C. elegans, 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 Drosophila 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 Drosophila. 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. Lactiplantibacillus is a potential source of butyrate, while Acetobacter produces acetate. Mono-association with Acetobacter or Lactiplantibacillus 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 Acetobacter and Lactiplantibacillus, 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: ABCA7, PSEN1, SORL1 and TREM2 . 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.
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 Drosophila, 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.
INTRODUCTION: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. CASE PRESENTATION:A 3-year-old child had been involuntarily grasping with one hand and then the other from infancy. His neuromotor development corresponded with that of his contemporaries. Identical unusual movements were also observed in his father, uncle, and grandmother within his family heritage. In the family where identical observations were noted throughout three generations, the mildest manifestations were reported in the grandmother, but our patient, the index case, had more significant symptoms. The quadruple WES study of the family indicated that all clinically symptomatic individuals harbored a nonsense mutation in the DCC gene. CONCLUSIONS:Mirror movements, typically identified in childhood, may result from genetic or neurological disorders. This study presents four individuals from the same family diagnosed with congenital mirror movement disorder.
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 Drosophila 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.
Genes play an important role in the risk of Progressive Supranuclear Palsy (PSP). Some of the major risk genes identified for PSP include MAPT, STX6, MOBP, and EIF2AK3 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 MAPT gene (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, rs7521, rs12185268, and rs62063857, and two SNPs of STX6 gene (rs3747957 and rs1411478), one SNP each from MOBP (rs1768208) and EIF2AK3 (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 MAPT gene (rs1467967, rs242557, rs3785883), along with STX6 (rs1411478) and MOBP (rs1768208), appeared to be the best five-locus model (p < 0.001), suggesting strong interactions among MAPT, STX6 and MOBP genes in modulating the risk of PSP. Strong synergistic interactions were observed within MAPT gene (rs1467967, rs244557, rs3785883, rs7521, and rs2471738), and between MAPT (rs7521) and MOBP (rs1768208). Additionally, moderately strong synergistic interactions were found between (i) MOBP (rs1768208) and STX6 (rs1411478), and (ii) MOBP (rs1768208) and MAPT (rs3785883) genes. The findings of this study suggest significant impact of gene-gene interactions amongst MAPT, STX6, and MOBP genes in modulating the risk of PSP. This implies that epistatic interactions might constitute an important mechanism in delineating the genetic basis of PSP.
Forgetting behavior is a common phenomenon that has been widely studied in various model organisms, including Caenorhabditis elegans (C. elegans), 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, C. elegans 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 (arx-1, arx-2, arx-3, arx-5, and arx-7) 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 arx-5 and arx-7 was observed, along with a reduction in arx-2::mCherry fluorescence in specific tissues of C. elegans. This study demonstrates that C. elegans 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 (arx-1, arx-2, arx-3, arx-5, and arx-7) are reduced, inhibiting cytoskeleton nucleation in cells. This inhibition may contribute to the observed pathogen-induced forgetting in C. elegans in response to PA14.
