Journal of neurogenetics最新文献

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.

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.

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.

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.

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 GABA_B agonist SKF-97541 reduced mortality, while GABA or GABA_A 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.

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.

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 APOE 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, TREM2, SORL1 and ABCA7. 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.

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.

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.