Selective Loss Research Articles

The loss of βΙ spectrin alters synaptic size and composition in the ja/ja mouse.

Deletion or mutation of members of the spectrin gene family contributes to many neurologic and neuropsychiatric disorders. While each spectrinopathy may generate distinct neuropathology, the study of βΙ spectrin's role (Sptb) in the brain has been hampered by the hematologic consequences of its loss. Jaundiced mice (ja/ja) that lack βΙ spectrin suffer a rapidly fatal hemolytic anemia. We have used exchange transfusion of newborn ja/ja mice to blunt their hemolytic pathology, enabling an examination of βΙ spectrin deficiency in the mature mouse brain by ultrastructural and biochemical analysis. βΙ spectrin is widely utilized throughout the brain as the βΙΣ2 isoform; it appears by postnatal day 8, and concentrates in the CA1,3 region of the hippocampus, dentate gyrus, cerebellar granule layer, cortical layer 2, medial habenula, and ventral thalamus. It is present in a subset of dendrites and absent in white matter. Without βΙ spectrin there is a 20% reduction in postsynaptic density size in the granule layer of the cerebellum, a selective loss of ankyrinR in cerebellar granule neurons, and a reduction in the level of the postsynaptic adhesion molecule NCAM. While we find no substitution of another spectrin for βΙ at dendrites or synapses, there is curiously enhanced βΙV spectrin expression in the ja/ja brain. βΙΣ2 spectrin appears to be essential for refining postsynaptic structures through interactions with ankyrinR and NCAM. We speculate that it may play additional roles yet to be discovered.

Calcium Deregulation in Neurodegeneration and Neuroinflammation in Parkinson's Disease: Role of Calcium-Storing Organelles and Sodium-Calcium Exchanger.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that lacks effective treatment strategies to halt or delay its progression. The homeostasis of Ca2+ ions is crucial for ensuring optimal cellular functions and survival, especially for neuronal cells. In the context of PD, the systems regulating cellular Ca2+ are compromised, leading to Ca2+-dependent synaptic dysfunction, impaired neuronal plasticity, and ultimately, neuronal loss. Recent research efforts directed toward understanding the pathology of PD have yielded significant insights, particularly highlighting the close relationship between Ca2+ dysregulation, neuroinflammation, and neurodegeneration. However, the precise mechanisms driving the selective loss of dopaminergic neurons in PD remain elusive. The disruption of Ca2+ homeostasis is a key factor, engaging various neurodegenerative and neuroinflammatory pathways and affecting intracellular organelles that store Ca2+. Specifically, impaired functioning of mitochondria, lysosomes, and the endoplasmic reticulum (ER) in Ca2+ metabolism is believed to contribute to the disease's pathophysiology. The Na+-Ca2+ exchanger (NCX) is considered an important key regulator of Ca2+ homeostasis in various cell types, including neurons, astrocytes, and microglia. Alterations in NCX activity are associated with neurodegenerative processes in different models of PD. In this review, we will explore the role of Ca2+ dysregulation and neuroinflammation as primary drivers of PD-related neurodegeneration, with an emphasis on the pivotal role of NCX in the pathology of PD. Consequently, NCXs and their interplay with intracellular organelles may emerge as potentially pivotal players in the mechanisms underlying PD neurodegeneration, providing a promising avenue for therapeutic intervention aimed at halting neurodegeneration.

Orexin increases the neuronal excitability of several brain areas associated with maintaining of arousal.

Orexin is exclusively produced in neurons localized within the lateral hypothalamic area (LHA) and perifornical area (PFA). Orexin has been identified as a key promotor of arousal. The selective loss of orexinergic neurons results in narcolepsy. It is known that the intrinsic electrophysiological properties are critical for neurons to perform their functions in corresponding brain regions. In addition to hypothalamic orexin, other brain nuclei are involved in the regulation of sleep and wakefulness. Quite a lot of studies focus on elucidating orexin-induced regulation of sleep-wake states and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that the orexinergic neurons exhibit spontaneous firing activity which is associated with the states of sleep-wake cycle. Orexin mainly exerts postsynaptic excitatory effects on multiple brain nuclei associated with the process of sleep and wakefulness. This review may provide a background to guide future research about the cellular mechanisms of orexin-induced maintaining of arousal.

Retinoic acid signalling regulates branchiomeric neck muscle development at the head/trunk interface.

Skeletal muscles of the head and trunk originate in distinct lineages with divergent regulatory programmes converging on activation of myogenic determination factors. Branchiomeric head and neck muscles share a common origin with cardiac progenitor cells in cardiopharyngeal mesoderm (CPM). The retinoic acid (RA) signalling pathway is required during a defined early time window for normal deployment of cells from posterior CPM to the heart. Here, we show that blocking RA signalling in the early mouse embryo also results in selective loss of the trapezius neck muscle, without affecting other skeletal muscles. RA signalling is required for robust expression of myogenic determination factors in posterior CPM and subsequent expansion of the trapezius primordium. Lineage-specific activation of a dominant-negative RA receptor reveals that trapezius development is not regulated by direct RA signalling to myogenic progenitor cells in CPM, or through neural crest cells, but indirectly through the somitic lineage, closely apposed with posterior CPM in the early embryo. These findings suggest that trapezius development is dependent on precise spatiotemporal interactions between cranial and somitic mesoderm at the head/trunk interface.

The evolving spectrum of complex inherited neuropathies.

Inherited peripheral neuropathies can be divided into those diseases in which peripheral neuropathy is the sole or main feature of the disease (Charcot-Marie-Tooth disease) and those in which peripheral neuropathy is just one feature of a more complex syndrome. In recent years there has been a substantial expansion in the number of genes associated with complex neuropathy syndromes. This review will focus on emerging themes in this group of diseases, namely the increasing number of diseases due to repeat expansions; the emergence of both recessive and dominant negative alleles in the same gene producing a common phenotype and diseases in which there is selective loss of the allele from haematopoietic stem cells making genetic diagnosis on blood derived DNA problematic. In this review we provide a practical approach to investigating and diagnosing patients with peripheral neuropathy as part of a complex syndrome and provide an updated table of the genes associated with this group of diseases.

Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disease characterized by selective loss of motor neurons in the brainstem and spinal cord. Several genetic factors have been associated to ALS, ranging from causal genes and potential risk factors to disease modifiers. The search for pathogenic variants in these genes has mostly focused on single nucleotide variants (SNVs) while relatively understudied and not fully elucidated is the contribution of structural variants, such as copy number variations (CNVs). Here, we applied an exon-centric aCGH method to investigate, in sporadic ALS patients, the load of CNVs in 131 genes previously associated to ALS. Our approach revealed that CNV load, defined as the total number of CNVs or their size, was significantly higher in ALS cases than controls. About 87% of patients harbored multiple CNVs in ALS-related genes, and 75% structural variants compromised genes directly implicated in ALS pathogenesis (C9orf72, CHCHD10, EPHA4, FUS, HNRNPA1, KIF5A, NEK1, OPTN, PFN1, SOD1, TARDBP, TBK1, UBQLN2, UNC13A, VAPB, VCP). CNV load was also associated to higher onset age and disease progression rate. Although the contribution of individual CNVs in ALS is still unknown, their extensive load in disease-related genes may have relevant implications for the diagnostic, prognostic and therapeutical management of this devastating disorder.

Modulating Vertebrate Physiology by Genomic Fine-Tuning of GPCR Functions.

G protein-coupled receptors (GPCRs) play a crucial role as membrane receptors, facilitating the communication of eukaryotic species with their environment and regulating cellular and organ interactions. Consequently, GPCRs hold immense potential in contributing to adaptation to ecological niches and responding to environmental shifts. Comparative analyses of vertebrate genomes reveal patterns of GPCR gene loss, expansion, and signatures of selection. Integrating this genomic data with insights from functional analyses of gene variants enables the interpretation of genotype-phenotype correlations. This review underscores the involvement of GPCRs in adaptive processes, presenting numerous examples of how alterations in GPCR functionality influence vertebrate physiology, or conversely, how environmental changes impact GPCR functions. The findings demonstrate that modifications in GPCR function contribute to adapting to aquatic, arid, and nocturnal habitats, influencing camouflage strategies, and specializing in particular dietary preferences. Furthermore, the adaptability of GPCR functions provides an effective mechanism in facilitating past, recent, or ongoing adaptations in animal domestication and human evolution and should be considered in therapeutic strategies and drug development.

Homeostatic Synaptic Plasticity of Miniature Excitatory Postsynaptic Currents in Mouse Cortical Cultures Requires Neuronal Rab3A.

Following prolonged activity blockade, amplitudes of miniature excitatory postsynaptic currents (mEPSCs) increase, a form of plasticity termed "homeostatic synaptic plasticity." We previously showed that a presynaptic protein, the small GTPase Rab3A, is required for full expression of the increase in miniature endplate current amplitudes following prolonged blockade of action potential activity at the mouse neuromuscular junction in vivo (Wang et al., 2011), but it is unknown whether this form of Rab3A-dependent homeostatic plasticity shares any characteristics with central synapses. We show here that homeostatic synaptic plasticity of mEPSCs is impaired in mouse cortical neuron cultures prepared from Rab3A-/- and mutant mice expressing a single point mutation of Rab3A, Rab3A Earlybird mice. To determine if Rab3A is involved in the well-established homeostatic increase in postsynaptic AMPA-type receptors (AMPARs), we performed a series of experiments in which electrophysiological recordings of mEPSCs and confocal imaging of synaptic AMPAR immunofluorescence were assessed within the same cultures. We found that Rab3A was required for the increase in synaptic AMPARs following prolonged activity blockade, but the increase in mEPSC amplitudes was not always accompanied by an increase in postsynaptic AMPAR levels, suggesting other factors may contribute. Finally, we demonstrate that Rab3A is acting in neurons because only selective loss of Rab3A in neurons, not glia, disrupted the homeostatic increase in mEPSC amplitudes. This is the first demonstration that neuronal Rab3A is required for homeostatic synaptic plasticity and that it does so partially through regulation of the surface expression of AMPA receptors.

Sex ratio at birth across 100 years in Sweden and risk of cardiovascular disease and all-cause mortality – a national register study

The human sex ratio at birth (SRB) undergoes temporary changes around a mean proportion of 0.51 male births. SRB has been well studied for historical, geographical, and secular trends, but until now not linked to health outcomes in the total population, e.g. for cardiovascular disease (CVD) or mortality during follow-up of birth cohorts. We used linkage analysis based on national registers in Sweden that cover all births from 1900 to 2016. SRB at birth was calculated by every 10-year birth cohort in all survivors living in 1997 for a follow-up analysis of risk of CVD and mortality with data from national registers. When the highest quartile of SRB was used as reference, a slightly increased risk of fatal CVD (HR 1.03 (95% confidence intervals, CI): 1.02–1.04), non-fatal CVD (HR 1.01; 95%CI: 1.01–1.02) and mortality (HR 1.02; 95%CI, 1.01–1.03) was found after full adjustments in men belonging to the lowest SRB quartile. A similar pattern was also found for fatal CHD in women. in the lowest SBR quartile compared to the highest, HR 1.03 (95%CI: 1.02–1.05). In conclusion, in birth cohorts with a relatively lower than expected number of males born, long-term adverse health effects were observed with slightly increased cardiovascular risk and total mortality at the population level. This could indicate that men belonging to so-called “culled cohorts” in a developed country during the 20th century are characterized by a slightly increased risk that could reflect negative early life influences and environmental exposures in pregnant women resulting in selective loss of male embryos or fetuses. In a public health perspective SRB could be of some importance to monitor as an aspect of birth statistics linked to relatively minor population health effects.

XGBoost-B-GHM: An Ensemble Model with Feature Selection and GHM Loss Function Optimization for Credit Scoring

Credit evaluation has always been an important part of the financial field. The existing credit evaluation methods have difficulty in solving the problems of redundant data features and imbalanced samples. In response to the above issues, an ensemble model combining an advanced feature selection algorithm and an optimized loss function is proposed, which can be applied in the field of credit evaluation and improve the risk management ability of financial institutions. Firstly, the Boruta algorithm is embedded for feature selection, which can effectively reduce the data dimension and noise and improve the model’s capacity for generalization by automatically identifying and screening out features that are highly correlated with target variables. Then, the GHM loss function is incorporated into the XGBoost model to tackle the issue of skewed sample distribution, which is common in classification, and further improve the classification and prediction performance of the model. The comparative experiments on four large datasets demonstrate that the proposed method is superior to the existing mainstream methods and can effectively extract features and handle the problem of imbalanced samples.

Diagnosis, treatment and management of lipodystrophy: the physician perspective on the patient journey

BackgroundLipodystrophy syndromes are a heterogeneous group of rare, life-limiting diseases characterized by a selective loss of adipose tissue and severe metabolic complications. There is a paucity of information describing the experiences and challenges faced by physicians who have seen and treated patients with lipodystrophy. This study aimed to provide a better understanding of the physician’s perspective regarding the patient journey in lipodystrophy, including diagnosis, the burden of disease, and treatment approaches.MethodsThirty-three physicians from six countries who had seen or treated patients with lipodystrophy were interviewed using a semi-structured questionnaire. Interviews were transcribed, anonymized, and analyzed for themes and trends. Four main themes were developed: (1) the diagnostic journey in lipodystrophy including the disease features or ‘triggers’ that result in the onward referral of patients to specialist medical centers with experience in managing lipodystrophy; (2) the impact of lipodystrophy on patient quality of life (QoL); (3) the use of standard therapies and leptin replacement therapy (metreleptin) in lipodystrophy, and (4) barriers to metreleptin use.ResultsParticipants reported that, due to their rarity and phenotypic heterogeneity, lipodystrophy cases are frequently unrecognized, leading to delays in diagnosis and medical intervention. Early consultation with multidisciplinary specialist medical teams was recommended for suspected lipodystrophy cases. The development and progression of metabolic complications were identified as key triggers for the referral of patients to specialist centers for follow-up care. Participants emphasized the impact of lipodystrophy on patient QoL, including effects on mental health and self-image. Although participants routinely used standard medical therapies to treat specific metabolic complications associated with lipodystrophy, it was acknowledged that metreleptin was typically required in patients with congenital generalized lipodystrophy and in some acquired generalized and partial lipodystrophy cases. A lack of experience among some participants and restrictions to access remained as barriers to metreleptin use.ConclusionsTo our knowledge, this is one of the first studies describing the qualitative experiences of physicians regarding the diagnosis and management of lipodystrophy. Other physician-centered studies may help increase the awareness of lipodystrophy among the wider medical community and support clinical approaches to this rare disease.

AC Micro Grid Fault Analysis

Implementation of micro grid concept creates several issues to the existing protection scheme in the radial distribution network. Depending on the location and capacity of the distributed generators, the short-circuit current from the main grid and distributed generations causes variations in the fault current levels inside the micro grid. The changes cause effect of sympathetic tripping, blinding of protection, relay over-reaching, relay under-reaching and loss of selectivity of the overcurrent protection scheme. Such issues must be managed carefully to ensure full benefit from micro grid adaptation. Conventional protection schemes are unable to detect fault current levels common in micro grid. Several methods have been proposed in various research paper. Micro grid protection is substantial to provide reliable and continuous power supply to the customers. The main aim of proposed work is to detect the fault for fast restoration of the system back to the normal operation. The proposed protection scheme for micro grid uses intelligent electronics device for detecting the fault

Recent Trends in Tailoring External Acidity in Zeolites for Catalysis.

Zeolites are crystalline aluminosilicates with well-defined microporous structures that have found several applications in catalysis. In recent years, great effort has been devoted to defining strategies aimed at tuning structural and acidity properties to improve the catalytic performance of zeolites. Depending on the zeolitic structure, the acid sites located inside the crystals catalyze reactions by exploiting the internal channel shape-selectivity. In contrast, strong acid sites located on the external surface do not offer the possibility to control the size of molecules involved in the reactions. This aspect generally leads to a loss of selectivity toward desired products and to the uncontrolled production of coke. Passivating surface acidity is a promising way to overcome deactivation issues and to enhance the catalytic performance of zeolites. This Mini-Review aims to provide, for the first time, a complete overview of the techniques employed in recent years to neutralize strong external acid sites. Both chemical and liquid vapor deposition of silicates have been widely employed to passivate the external surface acidity of zeolites. In recent years, the epitaxial growth of layers of aluminum-free zeolite, e.g., silicalite-1, over the surface of the acidic zeolite has been proposed as a new approach to neutralize strong external acid sites controlling diffusional phenomena. NH3-TPD, FT-IR, SEM-EDX, and other techniques have been used to provide information about the level of control of the external strong acidity of passivated zeolites. In this Mini-Review, both passivation treatments and characterization techniques are compared and advantages and disadvantages deeply discussed to elucidate the effect of passivation procedures on physical features and especially the catalytic behavior.

An Adaptive Noisy Label-Correction Method Based on Selective Loss for Hyperspectral Image-Classification Problem

Due to the intricate terrain and restricted resources, hyperspectral image (HSI) datasets captured in real-world scenarios typically contain noisy labels, which may seriously affect the classification results. To address this issue, we work on a universal method that rectifies the labels first and then trains the classifier with corrected labels. In this study, we relax the common assumption that all training data are potentially corrupted and instead posit the presence of a small set of reliable data points within the training set. Under this framework, we propose a novel label-correction method named adaptive selective loss propagation algorithm (ASLPA). Firstly, the spectral–spatial information is extracted from the hyperspectral image and used to construct the inter-pixel transition probability matrix. Secondly, we construct the trusted set with the known clean data and estimate the proportion of accurate labels within the untrusted set. Then, we enlarge the trusted set according to the estimated proportion and identify an adaptive number of samples with lower loss values from the untrusted set to supplement the trusted set. Finally, we conduct label propagation based on the enlarged trusted set. This approach takes full advantage of label information from the trusted and untrusted sets, and moreover the exploitation on the untrusted set can adjust adaptively according to the estimated noise level. Experimental results on three widely used HSI datasets show that our proposed ASLPA method performs better than the state-of-the-art label-cleaning methods.

Whole-genome landscape of histone H3K4me3 modification during sperm cell lineage development in tomato

BackgroundDuring male gametogenesis of flowering plants, sperm cell lineage (microspores, generative cells, and sperm cells) differentiated from somatic cells and acquired different cell fates. Trimethylation of histone H3 on lysine 4 (H3K4me3) epigenetically contributes to this process, however, it remained unclear how H3K4me3 influences the gene expression in each cell type. Here, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) to obtain a genome-wide landscape of H3K4me3 during sperm cell lineage development in tomato (Solanum lycopersicum).ResultsWe show that H3K4me3 peaks were mainly enriched in the promoter regions, and intergenic H3K4me3 peaks expanded as sperm cell lineage differentiated from somatic cells. H3K4me3 was generally positively associated with transcript abundance and served as a better indicator of gene expression in somatic and vegetative cells, compared to sperm cell lineage. H3K4me3 was mutually exclusive with DNA methylation at 3’ proximal of the transcription start sites. The microspore maintained the H3K4me3 features of somatic cells, while generative cells and sperm cells shared an almost identical H3K4me3 pattern which differed from that of the vegetative cell. After microspore division, significant loss of H3K4me3 in genes related to brassinosteroid and cytokinin signaling was observed in generative cells and vegetative cells, respectively.ConclusionsOur results suggest the asymmetric division of the microspore significantly reshapes the genome-wide distribution of H3K4me3. Selective loss of H3K4me3 in genes related to hormone signaling may contribute to functional differentiation of sperm cell lineage. This work provides new resource data for the epigenetic studies of gametogenesis in plants.

Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Aging is the biggest risk factor for the development of Alzheimer's disease (AD). Here, we performed a whole-genome CRISPR screen to identify regulators of neuronal age and show that the neddylation pathway regulates both cellular age and AD neurodegeneration in a human stem cell model. Specifically, we demonstrate that blocking neddylation increased cellular hallmarks of aging and led to an increase in Tau aggregation and phosphorylation in neurons carrying the APPswe/swe mutation. Aged APPswe/swe but not isogenic control neurons also showed a progressive decrease in viability. Selective neuronal loss upon neddylation inhibition was similarly observed in other isogenic AD and in Parkinson's disease (PD) models, including PSENM146V/M146V cortical and LRRK2G2019S/G2019S midbrain dopamine neurons, respectively. This study indicates that cellular aging can reveal late-onset disease phenotypes, identifies new potential targets to modulate AD progression, and describes a strategy to program age-associated phenotypes into stem cell models of disease.

Highly active palladium nanocatalyst for selective hydrogenation of 1,5-cyclooctadiene under atmospheric H2 pressure

An ionic liquid [CH3(OCH2CH2)22N+Et3][p-CH3C6H4SO3−] was synthesized and employed for stabilizing Pd nanocatalyst, which possesses the thermoregulated phase-separable property. The as-prepared Pd nanocatalyst was applied for the selective hydrogenation of 1,5-cyclooctadiene under atmospheric H2 pressure. The >99% conversion of 1,5-cyclooctadiene with 95% selectivity towards cyclooctene was achieved under the optimal reaction conditions. The Pd nanocatalyst could be reused for six cycles without evident loss in conversion and selectivity. The turnover frequency of 4232 h−1 is greater than those of previously reported Pd nanocatalyst under atmospheric H2 pressure.

Hydrogenation of the benzene rings in PET degraded chemicals over meso-HZSM-5 supported Ru catalyst

Chemical upcycling of waste polyethylene terephthalate (PET) to value-added products can reduce the emission of CO2, microplastics and toxic chemicals. In this work, mesoporous H-type Zeolite Socony Mobil-5 (HZSM-5) supported Ru catalyst (Ru/m-HZSM-5) was synthesized and tested in the hydrogenation of PET degraded chemicals (bis(2-hydroxyethyl) terephthalate, dimethyl terephthalate, diethyl terephthalate, and terephthalic acid). Characterizations disclosed that Ru/m-HZSM-5 catalyst possesses mesopores (a dominant channel of 5.32 nm), enlarged specific surface area (404 m2·g−1), and Ru NPs dispersed highly (40.6 %) compared to that of Ru/HZSM-5. And also, it was found that Ru/m-HZSM-5 was capable for the hydrogenation of benzene rings in these PET degraded chemicals with large sizes (1.09–1.82 nm). In particular, the conversion of BHET and the selectivity of BHCD over Ru/m-HZSM-5 reached 95.5 % and 95.6 % at 120 °C within 2 h. And Ru/m-HZSM-5 could be recycled at least five times without obvious loss of activity and selectivity.

A multi-population multi-stage adaptive weighted large-scale multi-objective optimization algorithm framework

Weighted optimization framework (WOF) achieves variable dimensionality reduction by grouping variables and optimizing weights, playing an important role in large-scale multi-objective optimization problems. However, because of possible problems such as duplicate weight vectors in the selection process and loss of population diversity, the algorithm is susceptible to local optimization. Therefore, this paper develops an algorithm framework called multi-population multi-stage adaptive weighted optimization (MPSOF) to improve the performance of WOF in two aspects. First, the method of using multi-population is employed to address the issue of insufficient algorithmic diversity, while simultaneously reducing the likelihood of converging towards local optima. Secondly, a processing stage is incorporated into MPSOF, where a certain number of individuals are adaptively selected for updating based on the weight information and evolutionary status of different subpopulations, targeting different types of weights. This approach alleviates the impact of repetitive weights on the diversity of newly generated individuals, avoids the drawback of easily converging to local optima when using a single type of weight for updating, and effectively balances the diversity and convergence of subpopulations. Experiments of three types designed on several typical function sets demonstrate that MPSOF exceeds the comparison algorithms in the three metrics for Inverse Generation Distance, Hypervolume and Spacing.

Lead specifically declines tyrosine hydroxylase activity to induce the onset of Parkinson's disease through disrupting dopamine biosynthesis in fly models

Parkinson's disease (PD) is one of the fastest-growing neurodegenerative diseases and has been linked to the exposure to numerous environmental neurotoxins. Although lead (Pb) exposure has been related to the development of PD, the molecular target of Pb to cause the onset of PD is insufficiently investigated. Herein, we explored the effects of Pb exposure on behavior, pathophysiology, and gene expression of wild-type (WT) fly (Drosophila melanogaster) by comparison with its PD model. After exposure to Pb, the WT flies showed PD-like locomotor impairments and selective loss of dopaminergic (DAergic) neurons, displaying similar phenotypes to fly PD model (PINK1). Transcriptomic analysis showed the similarity in gene expression profiles between Pb treatment WT flies and PINK1 mutant flies. Moreover, Pb exposure resulted in endogenous dopamine deficits in WT flies. Analyses of gene expression and enzyme activity confirmed that Pb exposure reduced tyrosine hydroxylase (TH) activity and led to failure of dopamine synthesis. Furthermore, molecular dynamics simulation confirmed that Pb was adsorbed by TH and subsequently inhibited the enzymatic activity. Exogenous injection of L-dopa and melatonin could partially rescue the pathological phenotypes of Pb-exposed flies and PD fly model. Antagonist injection of microRNA-133, which negatively regulated the expression of TH gene, ultimately rescued in the manifestation of PD phenotypes in flies. Involvement of TH overexpression mutants of fly strongly promoted the resistance to Pb exposure and rescued both behavior and the number of DAergic neurons. Therefore, our study elucidates the Pb molecular target in dopamine pathway and mechanism underlying the risks of Pb exposure on the occurrence of PD at environmentally-relevant concentrations.