Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is a leading cause of cancer death. G protein-coupled receptor 54 (GPR54) plays a role in cancer development by interacting with its endogenous ligand kisspeptin encoded by the KISS1 gene. However, the role of GPR54 in NSCLC development is not yet fully understood. Here, we demonstrate that GPR54 regulates NSCLC development via dopa decarboxylase (DDC). A mutant Kras-driven mouse lung cancer model revealed that adenoviral CMV-Cre-mediated Gpr54 deletion attenuated NSCLC development. Both Gpr54 deletion in mouse NSCLC tissues and GPR54 knockdown in human NSCLC cell lines caused apoptotic cell death. In addition, GPR54 regulation of NSCLC cell proliferation involves both the Gαq/11/AKT and β-arrestin/ERK signaling pathways. RNA sequencing revealed that Gpr54 deletion altered a gene set related to glycolysis and genotype-dependently regulated Ddc gene expression. Moreover, the regulation of glycolysis and DDC expression by GPR54 was dependent on the Gαq/11/PI3K/AKT/mTOR signaling pathway. Phosphoprotein arrays further revealed that DDC regulated NF-κB phosphorylation in NSCLC cells. Consistently, DDC regulated both NSCLC cell proliferation in vitro and tumor growth in vivo. Overall, our findings suggest that GPR54 could be a diagnostic marker for NSCLC and that therapeutics targeting GPR54 signaling may be useful for treating NSCLC.

Morphogen-driven melanin pathway dynamics regulated by Wnt1 and apontic-like underlie larval spot coloration in Bombyx mori.

PcncAAAD is a noncanonical fungal aromatic L-amino acid decarboxylase (AAAD) featuring a unique appendage C-terminal domain (CTD) and two metal-binding sites. Unlike its mammalian and plant counterparts, PcncAAAD is activated by calcium, although the exact activation mechanism remains unclear. Here, we establish an in silico RMSD-based evaluation model through molecular dynamics simulations, validated by in vitro enzyme assays, to decipher the enzyme's calcium activation mechanism. The metal-binding site at the intra-monomer interface between the N-terminal domain and the CTD (site A) is found to play a primary role in the calcium activation of PcncAAAD, whereas the secondary site within the unique CTD (site B) contributes to the calcium-mediated stabilization of enzyme structure. Binding of calcium, but not sodium, exerts a profound influence on PcncAAAD activity by stabilizing a "lid-rim" structure underlying site A, which in turn maintains the integrity of the substrate-binding environment. In silico mutations disrupting site A or the lid-rim structure show severe structural distortion of the active site, leading to reduced or even eliminated activity as demonstrated by in vitro assays. These findings deepen our understanding of metal-activatable enzymes and hold promise for the rational design of engineered enzymes for the synthesis of aromatic amino acid derivatives.

Accurate diagnosis of dementia with Lewy bodies (DLB) remains challenging, with misdiagnosis potentially leading to harmful treatment decisions. DOPA decarboxylase (DDC) shows promise as a cerebrospinal fluid (CSF) biomarker for DLB and Parkinson's disease (PD), but quantitative assays are needed for its clinical implementation. Here we report on the development of two DDC immunoassays and the extensive clinical validation of DDC across three clinical cohorts (n = 740), one biologically defined cohort (n = 253), one cohort with detailed dopamine transporter imaging information (n = 102) and one autopsy-confirmed cohort (n = 78). CSF DDC levels were significantly higher in DLB and PD (up to 2.5-fold versus controls; 1.9-fold versus AD), showing area under the curve values > 0.9 for differential diagnosis. Elevated CSF DDC was linked to the presence, but not severity, of motor impairment. In autopsy-confirmed DLB, higher CSF DDC correlated with progressing α-synuclein pathology and immunohistochemistry in DLB and PD brain tissue revealed colocalization of DDC and α-synuclein in the substantia nigra. These findings underscore DDC's value to support DLB and PD diagnosis, paving the way for its clinical implementation using the here-presented developed immunoassays.

DOPA decarboxylase levels in the cerebrospinal fluid as a diagnostic marker of Lewy body disorders.

BackgroundProteomic studies have identified cerebrospinal fluid (CSF) DOPA decarboxylase (DDC) as a promising biomarker candidate for Parkinson's disease (PD). The aim of this study was to develop an immunoassay for CSF DDC quantification and gain further insight into its potential as a biomarker for PD.MethodsWe validated our DDC immunoassay by quantifying CSF DDC levels in the Parkinson's Progression Markers Initiative cohort, including healthy controls (n = 29), dopaminergic drug-naïve PD patients (n = 27), and patients with scans without evidence for dopaminergic deficit (SWEDD) (n = 18).ResultsOur DDC assay detected elevated levels in CSF from dopaminergic drug-naïve PD patients and discriminated them against SWEDD patients and controls with high sensitivity and specificity. There was an inverse correlation between DDC levels and ioflupane-[123I]-single-photon emission computed tomography-based dopamine transporter (DaT-SPECT) striatal binding ratios (SBRs) from the putamen and caudate nucleus. CSF DDC levels demonstrated prognostic potential for Movement Disorder Society Unified Parkinson's Disease Rating Scale total score change five to eight years post-diagnosis. DDC levels were further increased at the three-year follow-up visit in PD patients and positively correlated with the L-DOPA equivalent daily dose. There was a strong correlation between the relative CSF DDC levels determined by a proprietary immune-based proximity extension assay and absolute levels determined with our assay.ConclusionsOur assay provided further insight into the potential of CSF DDC as a diagnostic and prognostic biomarker for PD. The unchanged levels in SWEDD patients and inverse correlation with DaT-SPECT SBRs suggest that CSF DDC levels are connected to dopaminergic deficit.

Dopa decarboxylase (DDC) is a crucial enzyme that regulates melanin synthesis and plays an essential role in cuticular pigmentation and insect development. However, the function of DDC in the fall armyworm, Spodoptera frugiperda, is not yet well understood. In this study, we knocked out the DDC gene and found that mosaic mutants displayed an albino phenotype across all life stages, including larval, pupal, and adult stages. Notably, homozygous DDC mutants showed complete larval albinism, exhibited developmental delays, and frequently failed to pupate, ultimately leading to death. Histological analyses revealed that tissue remodeling during metamorphosis was disrupted and became disorganized. A few individuals survived to adulthood, but they developed severely curled forewings. To clarify the molecular basis of these phenotypes, we performed a transcriptomic analysis and found that DDC influences pigmentation by regulating melanin-related and pteridine-related metabolic pathways. Additionally, DDC disruption altered the expression of genes involved in chitin metabolism and cuticular proteins, and affected the juvenile hormone and ecdysone signaling pathways. Overall, these results provide the first evidence that DDC is critical for pigmentation and development in S. frugiperda and shed new light on the molecular mechanisms underlying body color formation.

The molecular mechanisms by which insects perceive and behaviorally adapt to host plant nutritional variation constitute a fundamental question in insect-plant coevolution. The brown planthopper (Nilaparvata lugens, BPH), a monophagous pest of rice (Oryza sativa), exhibits striking wing dimorphism that directly governs its outbreak patterns: long-winged morphs (LW) initiate migration to escape low-quality hosts, while short-winged morphs (SW) drive local population explosions, thriving in high-quality hosts. However, the mechanism underlying this migration-residence behavior in response to host plant senescence remains unclear. Here, we identified early 4th and early 5th instars as sensitive stages in response to the yellow-ripe rice, a phenological stage marking the onset of host plant senescence that must be promptly avoided. High-performance liquid chromatography (HPLC) revealed that serotonin (5-HT) levels were significantly increased in BPHs during the sensitive stages. Exogenous administration of 5-HT and its precursor 5-hydroxytryptophan (5-HTP) significantly promoted long-winged morph development, whereas pharmacological inhibition with α-methyltryptophan (AMTP, a serotonin synthesis inhibitor) attenuated the wing dimorphism response to yellow-ripe rice. Identification and functional analysis of 5-HT synthesis pathway enzymes suggested that tryptophan hydroxylase (NlTRH) and aromatic L-amino acid decarboxylase (NlAADC) regulated the expression of insulin-like peptide 3 (NlIlp3), subsequently regulating the expression of insulin receptors 1 and 2 (NlInR1, NlInR2), which control wing dimorphism. In contrast, phenylalanine hydroxylase (NlPAH) showed no involvement. This study highlights the vital role of serotonin in wing dimorphism of BPH in response to host plant senescence and offers new targets for sustainable control of the pest.

Adeno-associated virus (AAV) vectors have taken center stage for gene therapy and have shown clinical efficacy in 15 human diseases to date. The Food and Drug Administration has approved seven AAV "drugs" for one-time treatment respectively for Leber's congenital amaurosis, spinal muscular atrophy, hemophilia B, Duchenne muscular dystrophy, hemophilia A, and aromatic L-amino acid decarboxylase deficiency. Despite these remarkable developments, it has become increasingly clear that the first generation of AAV vectors is less than optimal since in most, if not all, cases, exceedingly high doses are needed to achieve clinical efficacy, and as a consequence, in some patients, serious adverse events have been observed, and to date, at least 21 patients have died. Thus, there is a need to reassess the limitations of the first generation of AAV vectors as well as an urgent need to develop the next generation of AAV vectors that are safe and effective.

RNA interference targeting tyrosine hydroxylase and dopa decarboxylase inhibits the reproduction and survival in the small brown planthopper Laodelphax striatellus: A promising strategy for pest control.

Active tyrosine hydroxylase mutant in genome-edited mice leads to lower enzyme levels in the striatum.

The human gut microbiota plays a key role in neurochemical communication, especially through the gut-brain axis. There is growing evidence that the gut microbiota influences dopamine metabolism through both production and consumption mechanisms. Two key bacterial enzymes are central to this process: tyrosine decarboxylase (TDC), which primarily catalyzes the decarboxylation of tyrosine to tyramine but can also act on L-DOPA to produce dopamine in certain bacterial strains, and aromatic L-amino acid decarboxylase (AADC), which can convert precursors such as L-DOPA, tryptophan, or 5-hydroxytryptophan into bioactive amines including dopamine, tryptamine, and serotonin. Identifying the bacterial families corresponding to TDC and AADC enzymes opens new avenues for clinical intervention, particularly in neuropsychiatric and neurodegenerative disorders, such as Parkinson's disease. Moreover, elucidating strain-specific microbial contribution and host-microbe interactions may enable personalized therapeutic strategies, such as selective microbial enzyme inhibitors or tailored probiotics, to optimize dopamine metabolism. Emerging technologies, including biosensors and organ-on-chip platforms, offer new tools to monitor and manipulate microbial dopamine activity. This article explores the bacterial taxa capable of producing or consuming dopamine, focusing on the enzymatic mechanisms involved and the methodologies available for studying these processes in vivo.

Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic serotonin axis as key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4. Mechanistically, high level of intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives induced NE differentiation and is associated with suppressed androgen receptor signaling. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.

As global animal husbandry begins to reduce the use of antibiotics, finding safe and effective alternatives to antibiotics has become the key to ensuring the healthy and sustainable development of the industry. Probiotics are regarded as one of the most potential alternative strategies because of their functions of regulating intestinal microecological balance and inhibiting pathogenic bacteria. This study was performed to determine the potential probiotic Enterococcus faecalis strains from the feces of healthy lambs. One hundred and fifty-one rectal swabs were collected. BHI (brain heart infusion) medium was used to isolate target E. faecalis strains, and 16S rRNA was used to identify the type of bacteria. The potential probiotic strain (L118) with high acid resistance and negative for hemolytic and gelatinase activitys was selected and its characteristics including amino acid decarboxylase activity, virulence and antibiotic resistance, bacterial adhesion to solvents, aggregation capability and cellulase and amylase activitys were determined. In addition, animal feeding experiments were conducted about the candidate bacteria in goats. A non-hemolytic and gelatinase-negative strain (L118), with a high survival rate in simulated gastric fluid (pH 3.0) and simulated intestinal fluid, was screened from 151 strains of E. faecalis. At the same time, arginine decarboxylase activity and susceptibility to antibiotics such as penicillin, amikacin, vancomycin were observed. Also, L118 displayed high hydrophobicity, low auto-aggregation ability, and strong co-aggregation capacity with pathogenic bacteria (Salmonella typhimurium, Staphylococcus aureus). It also has cellulase and amylase activities. Meanwhile, E. faecalis L118 increased the red blood cells and hemoglobin content in the blood, serum glutathione peroxidase activity and intestinal lactobacillus (P < 0.05). An E. faecalis strain with high acid resistance was confirmed to possess safety and probiotic properties and provides an application and development of a new feed probiotic additive.

The thalamus plays a crucial role in integrating subcortical inputs and relaying them to cortical circuits, yet the extent and specificity of dopaminergic innervation to human thalamic nuclei remain incompletely understood. Recent tractographybased studies suggest the existence of direct nigro-thalamic pathways, but direct histological evidence is still limited. In this study, we provide an ex vivo mapping of dopaminergic projections to the human thalamus using high-resolution immunohistochemistry and confocal microscopy. Human brain specimens were processed to detect multiple dopaminergic markers, including tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and aromatic L-amino acid decarboxylase (AADC), across anatomically defined thalamic nuclei. Multilabel immunofluorescence and 3D reconstruction allowed precise identification of axonal arborization and synaptic varicosities within the mediodorsal (MD), and ventral anterior (VA)/ventral lateral (VL) nuclei. Quantitative analysis revealed a significant expression of TH+/VMAT2+ fibers and D2R staining in the MD/VA/VL nuclei, supporting the notion of region-specific dopaminergic input. These results provide the first immunohistological confirmation of selective dopaminergic innervation of the human thalamus. This structural evidence complements prior neuroimaging findings and suggests a potential role for the nigro- thalamic pathway in modulating thalamo-cortical circuits involved in executive and cognitive functions.

The predictive value of plasma biomarkers for phenoconversion in idiopathic REM sleep behavior disorder (iRBD) remains uncertain. To evaluate the utility of plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and DOPA decarboxylase (DDC) levels for predicting phenoconversion in iRBD. Fifty patients with polysomnography-confirmed iRBD and 38 matched healthy controls (HCs) were prospectively enrolled. Plasma NfL and GFAP were measured using SIMOA at baseline and after phenoconversion, and DDC levels via ELISA. Clinical assessments included UPDRS III, MMSE, MoCA, Geriatric Depression Scale, and SCOPA-AUT, and prodromal markers predictive of phenoconversion. Over 3.7years, 22 patients phenoconverted (7 multiple system atrophy [MSA]; 15 Lewy body diseases [LBDs]). Baseline NfL levels were higher in converters (median, 14.00pg/mL), especially MSA converters (16.10pg/mL), than in non-converters (11.15pg/mL) and HCs (11.55pg/mL) (p = 0.025 and p = 0.009, respectively). Baseline GFAP and DDC levels did not differ. In MSA converters, NfL correlated with SCOPA-AUT score (r = 0.925, p = 0.008), and a cutoff of 12.60pg/mL predicted MSA phenoconversion (sensitivity 100%, specificity 62.8%, AUC = 0.83, p = 0.003). Post-phenoconversion NfL levels were elevated in converters (18.80pg/mL) than in non-converters (13.05pg/mL) (p < 0.001), highest in MSA converters (24.45pg/mL; p < 0.001). GFAP showed a marginal increase (p = 0.051), while DDC showed no significant differences. Plasma NfL is a promising biomarker for predicting phenoconversion in iRBD, particularly to MSA, and may reflect underlying autonomic dysfunction.

To evaluate the impact of supraclinical doses of carbidopa on the pharmacokinetics and pharmacodynamics of levodopa in rat and monkey models of Parkinson's disease and to assess the causes for the insufficiency of dihydroxyphenylalanine (DOPA) decarboxylase inhibition at the clinical dose of carbidopa. The effects of supraclinical doses of carbidopa and entacapone, a catechol-O-methyltransferase inhibitor, were compared with those of equivalent clinical doses in Parkinson's disease models. Pharmacological assessments were conducted using 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. DOPA decarboxylase levels in the human liver, human kidney, and rat liver were quantified. Supraclinical doses of carbidopa extended the plasma half-life of levodopa in rats, whereas high-dose entacapone did not. Prolonged and sustained pharmacological effects of levodopa were observed in both Parkinson's disease models with supraclinical doses of carbidopa (80-fold and 200-fold greater than the clinical equivalent in rats and marmosets, respectively). DOPA decarboxylase levels in the human liver, human kidney, and rat liver were estimated to be in the submicromolar range, comparable to or exceeding plasma carbidopa concentrations at the clinical dose. High-dose carbidopa co-administration is a promising approach to achieve sustained clinical efficacy of levodopa while mitigating the risk of motor complications.

BackgroundLewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are neurodegenerative disorders that often overlap with Alzheimer's disease (AD), complicating diagnosis and patient management. The role of α‐synuclein aggregation in LBD and its interplay with AD pathology remains unclear. Biomarkers like DOPA decarboxylase (DDC) have shown promise in differentiating healthy controls, PD, and AD. However, molecular mechanisms underlying disease heterogeneity in LBD require further investigation. Here we examine proteomic differences associated with α‐synuclein pathology and its clinical manifestations, including cognitive decline and parkinsonism symptoms.MethodWe analyzed 1,388 proteins from CSF Olink of 915 participants from the Swedish BioFINDER‐2 cohort, incorporating CSF α‐synuclein seeding amplification assays (SAA) and AD pathology biomarkers (p‐tau181/Aβ42). Participants were classified as cognitively unimpaired or impaired (MCI/dementia) and by the presence of parkinsonism. Associations between CSF proteins and SAA pathology, cognitive status, and parkinsonism were assessed using a single linear regression model, adjusting for age, sex, and mean protein levels. Differentially abundant proteins (DAP) across the three conditions (pFDR<0.05) were further evaluated after adjusting for AD pathology. Functional and cell‐type enrichment analyses were performed upregulated and downregulated DAPs separately across conditions. We then identified proteins included in the resulting biological and cellular processes to assess in which conditions they were abundant.ResultAmong 287 SAA+ participants, 110 had parkinsonism symptoms, 198 had cognitive impairment, and 51 were clinically unimpaired (Table 1). We identified 129 DAPs across all conditions: 82 remaining significant after adjusting for AD pathology (Figure 1). Most DAPs were linked to cognitive status, with minimal overlap across conditions (Figure 1B). Downregulated proteins were enriched in synaptic processes, particularly neuronal signaling, cell junction assembly, and axonogenesis (Figure 2). Notably, DDC was consistently upregulated across all conditions, and neuropeptide Y (NPY), involved in stress responses, was consistently downregulated.ConclusionWe identified specific molecular processes in LBD and their interplay with cognitive and motor symptoms, independently of AD pathology. These suggest disruptions in synaptic and cellular regulation. Furthermore, neuropeptides such as NPY may play a neuroprotective role in LBD. These findings contribute to understanding LBD pathophysiology and identifying potential therapeutic targets.

Unveiling enantioselective mechanisms of toxicity of butylone in Daphnia magna.

From rodents to humans: Conserved codistribution of dopaminergic with serotonergic neurons in the dorsal raphe nucleus and their molecular characterization.