Search Results (7,816)

Objectives: Adults exposed to the Bacillus Calmette–Guérin (BCG) vaccine demonstrate a reduced incidence of Parkinson’s disease (PD). This retrospective study evaluated whether early-life BCG vaccination predicts a long-term reduction in PD incidence during aging. Methods: Published age-adjusted incidence rates (AAIRs) of PD (2002–2021) were structured into single-age birth cohorts. Missing values were calculated via interpolation and shuffling simulations. Cohorts were categorized into three historical BCG policy periods: unvaccinated controls (born 1945–1949), vaccinated at age 12 (born 1950–1954), and vaccinated as newborns (born 1955–1959). AAIRs were compared at identical cross-sectional ages (57 and 62 years), applying an environmental drift penalty to control for temporal improvements. Results: In men, the age 12 policy showed a 21.8% AAIR reduction at age 57, which attenuated to 4.4% by age 62; the newborn policy showed a sustained reduction (25.8% at age 57; 20.4% at age 62). In women, the age 12 policy yielded a 67.5% reduction at age 57 (33.1% at age 62), while the newborn policy showed a 56.8% reduction at age 57 (44.0% at age 62). Conclusions: Early-life BCG vaccination is associated with reduced later-life PD incidence, displaying a profound sex-dependent effect favoring females. Newborn vaccination provides long-term resistance as well. Full article

Parkinsonian syndromes comprise overlapping neurodegenerative and non-degenerative disorders, making aetiological diagnosis difficult, while existing procedural guidance does not fully integrate tracer-specific biology with clinical decision-making, multimodal strategies, and emerging quantitative and pathology-directed biomarkers. This review synthesises evidence on the molecular targets, radiopharmaceutical characteristics, biological interpretation, and clinical applications of dopaminergic single-photon emission computed tomography (SPECT) and positron emission tomography (PET), focusing on the dopamine transporter (DAT), aromatic L-amino acid decarboxylase (AADC), vesicular monoamine transporter type 2 (VMAT2), dopamine D₂/D₃ receptors, differential diagnosis, semiquantification, kinetic modelling, and artificial intelligence-assisted interpretation. The evidence confirms that DAT SPECT with [¹²³I]ioflupane ([¹²³I]FP-CIT) remains the most established method for demonstrating or arguing against presynaptic nigrostriatal dysfunction, but an abnormal result cannot establish aetiology, and a normal result can redirect evaluation towards non-degenerative mimics; target-specific PET provides complementary biological information, although availability, standardisation, and prospective validation remain limiting. By additionally integrating genetic and prodromal applications, question-driven multimodal imaging, emerging acquisition approaches, α-synuclein imaging and seed amplification assays, and contemporary biological staging frameworks, this review extends procedural guidance and positions dopaminergic imaging as a targeted functional biomarker selected according to the unresolved clinical question rather than as a stand-alone disease label. Full article

Curcumin and natural curcuminoids possess numerous beneficial properties, including antioxidant, antitumor, and anti-inflammatory effects. However, their application is challenging because of instability and rapid metabolism. Cyclic C₅-curcuminoids, a subgroup of curcuminoids, are chemically more stable and less susceptible to hydrolysis or metabolism. In our study, seven synthetic compounds—five cyclic C₅-curcuminoids (compounds 8, 9, 11, 12, and 13) and two cyclic chalcones (compounds 4 and 5)—were examined using an in vitro 6-hydroxydopamine-induced neuronal damage model established with all-trans retinoic acid-differentiated SH-SY5Y and BV-2 microglial cells. The antioxidant, anti-apoptotic (including ferroptosis markers (iron, GSH/GSSG, and malondialdehyde)), apoptotic (PARP, cytochrome c, caspase 9, active caspase-3, and oligonucleosome release), and anti-inflammatory effects of these compounds were also investigated. Compounds 5, 9, 12, and 13 significantly decreased reactive oxygen species production (percentage changes: 5: 28.9%; 9: 32%; 12: 29.8%; 13: 49.2%) and increased antioxidant capacity (percentage changes: 5: 63.4%; 9: 85.8%; 12: 31.2%; 13: 85.9%) and antioxidant enzyme activity (catalase, superoxide dismutase, and glutathione peroxidase) in SH-SY5Y cells. Compounds 5, 9, and 12 decreased microglial activation by downregulating Iba1 expression (fold changes: 5: 0.73; 9: 0.39; 12: 0.33) and decreasing glutamate concentration (percentage changes: 5: 26.5%; 9: 41.2%; 12: 27.3%). Together with compound 13, they reduced pro-inflammatory cytokine (IL-6, TNFα) secretion and induced anti-inflammatory cytokine (IL-10) release in SH-SY5Y and BV-2 cells. Based on these results, the blood–brain barrier penetrations of compounds 5, 9, 12, and 13 were also investigated. The highest blood–brain barrier penetration was observed for compound 12 (P_app value 13.6 × 10⁻⁶ cm/s). Synthetic cyclic C₅-curcuminoids derived from curcumin overcome the limitations of stability and bioavailability and exhibit strong antioxidant, anti-inflammatory, and anti-apoptotic effects, making them promising candidates for treating neurodegenerative diseases. Full article

Both RIT1 and RIT2 are members of the RAS superfamily of small GTPases, which regulate various cellular processes. RIT1 is widely expressed, whereas RIT2 is primarily found in neuronal tissues. Dysregulation of these proteins has been associated with several human diseases, including Noonan syndrome, cancer, Parkinson’s disease, autism, and schizophrenia. Although RIT1 and RIT2 are often compared to classical RAS proteins, they exhibit distinct regulatory and biochemical properties. Here, we demonstrate that RIT1 differs from classical RAS in GTPase cycling. Unlike classical RAS proteins, RIT1 did not respond to SOS1-mediated nucleotide exchange or p120GAP-stimulated GTP hydrolysis under cell-free conditions. These results imply that RIT1 may depend on regulatory mechanisms that differ from those of classical RAS proteins. However, the relevant physiological regulators remain unknown. Disease-associated RIT1 mutations cluster around the P-loop and Switch II regions. In this transient overexpression screening system, however, these mutations had only a modest effect on the canonical MAPK, PI3K/AKT, and JNK signaling pathways in HEK293T overexpression experiments. This suggests the existence of additional context-specific effectors and regulatory factors. We demonstrate that RIT1 and RIT2 interact with membrane lipids via a basic C-terminal extension. The KRLK-containing region contributes to the binding of phosphatidylserine and phosphoinositides. Charge-reversal mutations disrupt lipid interactions and liposome binding, supporting the functional importance of this region. In a reconstituted liposome system, galectin-3 and LZTR1, but not galectin-1, reduced the interaction of GDP-loaded RIT1 and RIT2 with liposomes. These results suggest that accessory proteins may influence RIT membrane interactions. However, their cellular relevance requires further validation. Together, our findings provide biochemical insights into RIT GTPase regulation and its interactions with membrane lipids under cell-free conditions. Full article

The discovery of the glymphatic system and meningeal lymphatic vessels established that the brain possesses an organized lymphatic clearance network that drains to the deep cervical lymphatics. Disruption of this system has been suggested to contribute to the accumulation of pathogenic proteins implicated in neurodegeneration. Cervical lymphatic reconstruction has been associated with some neurological benefit in Alzheimer’s and Parkinson’s disease, and preclinical work has demonstrated that noninvasive manipulation of superficial cervical lymphatics can increase cerebrospinal fluid outflow. Whether noninvasive cervicofacial lymphedema therapy can produce comparable neurological effects remains unknown. We report two men with Parkinson’s disease (Hoehn and Yahr stages 2.5 and 3) treated with a standardized cervicofacial lymphedema therapy protocol targeting cervical and facial lymphatic pathways. Total MDS-UPDRS scores decreased by 19 points (34.5%) in Patient 1 and 5 points in Patient 2. The reduction in Patient 1 exceeded the published threshold for clinically meaningful total-score improvement. Benefits were reproducible and session-linked, and were accompanied by motor and non-motor gains in cognition, alertness, mood, energy, and sleep; interruption of therapy was associated with return toward baseline. Cervicofacial lymphedema therapy may represent a low-risk, noninvasive intervention hypothesized to influence brain lymphatic clearance in Parkinson’s disease. Full article

Dysregulation of target genes of nonsense-mediated decay (NMD) in the brain remains sparsely known in tauopathies. PS19 transgenic mice expressing human mutant P301S tau were evaluated for levels of lncRNA Gas5, a target of NMD. The results show Gas5 decreased in the brains of PS19 mice as they aged. We evaluated the consequences of blocking the NMD-mediated turnover of Gas5 using a small molecule administered intranasally to PS19 mice. The results show NPC86 disassociated Upf1 and Gas5, thereby hindering NMD. NPC86 treatment increased Gas5 levels in the cortex of male PS19 mice concurrent with a highly significant decrease in pTau S214 and neuroinflammatory genes while increasing insulin signaling. Consequently, digital spatial profiling identified Gas5-regulated genes and pathways. NPC86 treatment enhanced neuronal homeostasis, synaptic vesicle transport and mitochondrial function and downregulated neuroinflammatory pathways. The nodal genes in Parkinson’s signaling pathway, the multiple sclerosis signaling pathway, the Gα(s) signaling pathway, the neuroinflammation signaling pathway, and the interferon gamma signaling pathway were decreased in response to NPC86. The study demonstrates the potential of selectively stabilizing NMD-target lncRNA Gas5 levels to alleviate early neurodegenerative pathology in tauopathy. Full article

Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action—paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs—while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood–brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies—MSCs as adjuncts to gene or enzyme replacement therapy—and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice. Full article

Heritability in Parkinson’s disease (PD) may be driven by rare variants (RVs), but genetic data for Chinese cohorts remain limited. We investigated the relationship between RVs and the risk and phenotype of PD by performing targeted exome sequencing of 29 PD candidate genes in 311 late-onset, sporadic Chinese PD patients and 699 local controls. A total of 174 RVs (that were likely deleterious using in silico prediction tools) were identified in 27 of the 29 genes sequenced. Mean RV burden was higher (1.178 vs. 0.478, p = 1.26 × 10⁻²⁴) and HLA-DRB5 p.Val104ArgfsTer26 was enriched in PD patients (0.207 vs. 0.000, p < 0.0003) compared with controls. Gene-based RV carrier status in PD patients was then examined for correlation with phenotypic characteristics. The RV carrier status of LRRK2 and HLA-DRB5 was associated with tremor, SREBF1 with gait disturbance, and SYNJ1 and SCARB2 with motor fluctuations. Earlier onset age and neuropsychiatric symptoms were associated with GBA1 variants. Olfactory deficit, autonomic disturbance, anxiety and depression were associated with variants in SLC44A1, HLA-DRB5, and SCARB2 respectively. Our results demonstrated a prominent RV burden in Chinese PD and illustrated the importance of genetic influence on the risk and phenotype of sporadic PD. Further studies are warranted to correlate these genes with putative pathogenic pathways. Full article

Background: Diabetic retinopathy (DR) and Parkinson’s disease (PD) are prevalent, progressive disorders that cause irreversible visual impairment and motor dysfunction, respectively. Increasing evidence suggests that retinal alterations may precede and predict neurodegeneration in PD, indicating potential shared pathogenic mechanisms. This study aimed to delineate the molecular and cellular connections between DR and PD, with a particular focus on their convergent neuroimmune and vascular pathways. Methods: We integrated single-cell RNA sequencing (scRNA-seq) datasets derived from proliferative DR (PDR) retinal fibrovascular membranes and PD brain tissues. Cell-type-associated transcriptional features were identified within each dataset, and corresponding cell populations were compared to identify candidate overlapping molecular features. CellChat was used to infer potential ligand–receptor interactions between cell populations. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to explore associated biological pathways and transcriptional programs. Results: A2M, NRP1, and ETS2 were identified as candidate shared transcriptional features in corresponding microglial and endothelial cell populations across the PDR and PD datasets. CellChat analysis predicted an ITGB2–ICAM1 (integrin beta-2-Intercellular Adhesion Molecule 1) ligand–receptor interaction in both datasets, although the predicted sender–receiver relationships differed according to tissue context. GSEA and GSVA identified overlapping inflammatory, apoptotic, hypoxia-related, and epithelial–mesenchymal transition-associated transcriptional programs across the analyzed datasets. These findings suggest potentially convergent immune–vascular and inflammatory features between PDR and PD. Conclusions: This exploratory single-cell analysis identified candidate cell-type-associated transcriptional features and potential cell–cell communication patterns shared between PDR and PD. The predicted ITGB2–ICAM1 interaction provides a hypothesis for further investigation of immune–vascular communication. Full article

Leucine-rich repeat kinase 2 (LRRK2) has emerged as a central molecular node linking genetic risk, membrane trafficking, lysosomal homeostasis, and immune signalling in Parkinson’s disease (PD). Rather than functioning as a conventional protein kinase, LRRK2 operates as a conformationally regulated, Rab-directed signalling machine whose activity is governed by long-range interdomain communication, membrane recruitment, and cooperative interactions with small GTPases. Converging advances in cryo-electron microscopy, quantitative phosphoproteomics, and human genetics indicate that pathogenic mutations, lysosomal stress, and pharmacological inhibitors do not simply alter catalytic output, but reshape the conformational landscape of LRRK2, biasing it toward distinct structural states with divergent cellular consequences. A defining feature of this system is the selective phosphorylation of Rab GTPases at low stoichiometry—most prominently Rab8 and Rab10—yet with disproportionate functional impact on vesicle trafficking, ciliogenesis, autophagy, and organelle positioning. The identification of Rab-directed phosphatases, particularly PPM1H, further establishes that LRRK2 signalling is governed by a dynamically balanced kinase–phosphatase circuit operating in space and time. These observations, together with emerging evidence linking LRRK2 activation to lysosomal damage and immune pathways, support a unifying hypothesis: PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent trafficking and organelle homeostasis, rather than from kinase hyperactivity alone. In this review, we integrate structural, biochemical, and cellular evidence to advance this framework and discuss its implications for disease mechanisms and therapy. We highlight key unresolved challenges—including conformation-selective drug targeting, spatial control of Rab phosphorylation, and context-dependent immune–neuronal crosstalk—and propose that restoring physiological regulation of LRRK2, rather than simply inhibiting its activity, will be essential for achieving mechanism-based disease modification in Parkinson’s disease. Full article

Objectives: Non-pharmacological therapies are a cornerstone of Parkinson’s disease (PD) treatment, but there is not enough evidence of their benefit when delivered altogether online. Our objective was to analyze the efficacy and safety of an online comprehensive care therapy program (OL-CCTP) in people with PD (PwP). Material and methods: This was a proof-of-concept experimental, prospective, 6-month interventional study comparing a PD treatment group (PwP-T) with a control group (PwP-C). The OL-CCTP included group sessions of physical therapy/therapeutic exercise, nutrition, speech therapy, cognitive stimulation, and psychological support (126 sessions over 6 months). The primary outcome was the change in quality of life at 6 months, as measured by the PDQ-39 questionnaire. Mood (Beck Depression Inventory-II [BDI-II]), the non-motor symptom burden (Non-Motor Symptoms Scale [NMSS]), and disability (Schwab and England Activities of Daily Living Scale [ADLS]) were also assessed. Results: Sixty patients (36 PwP-T and 24 PwP-C) completed the assessments. A reduction of 12.9% (from 78.4 ± 17.9 to 68.3 ± 18.7; p < 0.0001) was observed in the PDQ-39 total score in the PwP-T group (p < 0.0001), compared to 1.5% (from 77.8 ± 22.2 to 76.6 ± 27.9; p = 0.438) in the PwP-C group (p = 0.009). The BDI-II and NMSS scores decreased significantly by 13.1% (p = 0.001) and 20.3% (p = 0.046), respectively, in the PwP-T group but not in the PwP-C group. There were no significant changes in ADLS in either group. No adverse events were reported. Conclusions: After 6 months of OL-CCTP, an improvement of 12.9% was observed in the quality of life of patients with PD. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) develop over decades, yet their earliest pathogenic drivers remain poorly understood. Epidemiological and experimental animal studies suggest that disturbances in oral sensorimotor regulation, particularly within trigeminal proprioceptive pathways, may contribute to neural dysfunction long before clinical symptoms emerge. The mesencephalic trigeminal nucleus (MesV), the only primary sensory neuron population located entirely within the central nervous system (CNS), links oral proprioception with brainstem and forebrain networks. Chronic occlusal mismatch, impaired mastication, sleep bruxism, and sleep-disordered breathing may generate persistent sensorimotor prediction errors that destabilize MesV-centered circuits and subsequently recruit the locus coeruleus (LC), the brain’s principal noradrenergic stress nucleus. This review proposes an oral–brain axis model in which chronic MesV-related prediction error signaling engages LC-dependent stress systems, leading to neuroimmune activation, locus coeruleus–asparagine endopeptidase (LC-AEP) pathway engagement, and downstream proteinopathic processes. Sustained LC activity may facilitate microglial priming, reactive astrocytosis, and neuroinflammatory signaling, creating conditions that favor LC-AEP pathway activation and downstream tau pathology. Epidemiological studies associate tooth loss, reduced occlusal support, and impaired mastication with increased dementia risk, while experimental models of prodromal PD demonstrate early trigeminal sensory-processing abnormalities preceding motor symptoms. Together, these findings support the hypothesis that chronic disturbances in oral sensorimotor homeostasis may increase neurodegenerative vulnerability. This framework identifies potential biomarkers and preventive targets, suggesting that modulation of oral function and neuroimmune pathways may help reduce neurodegenerative risk before irreversible neuronal loss occurs. Full article

Objectives: The pathological progression of Parkinson’s disease (PD) involves alterations across multiple neural cell types, and glial–neuronal communication substantially influences neuronal function. Oligodendrocytes (OLs) have been implicated in PD pathology, but the underlying regulatory mechanisms remain incompletely understood. Methods: In this study, single-nucleus RNA sequencing and spatial transcriptomics were used to characterize OL-associated changes and explore potentially relevant mechanisms in the substantia nigra pars compacta (SNpc) of MPTP-induced parkinsonian mice. Molecular validation was subsequently performed in an exercise intervention cohort. Results: These analyses revealed a significant reduction in OL abundance in the SNpc, accompanied by enrichment of ferroptosis-related pathways. Aerobic exercise partially restored the expression of the OL marker gene Plp1 and the antioxidant pathway-related molecules Nrf2 and Gpx4, while reducing ferroptosis-related oxidative stress. These changes were associated with improvements in PD-like pathological phenotypes. Exploratory untargeted metabolomics further identified candidate alterations in metabolites and pathways related to redox homeostasis, energy metabolism, and myelin-associated processes after MPTP treatment and exercise intervention. Conclusions: Collectively, exercise-associated improvements in MPTP-induced PD-like phenotypes coincided with reductions in OL/myelin-related injury and ferroptosis-related stress. These findings suggest that OL-associated ferroptosis-related stress may represent one of several processes contributing to neuronal injury in PD and may be responsive to aerobic exercise. This study provides a theoretical basis for further investigation of exercise-based rehabilitation strategies and potential therapeutic targets for PD. Full article

Parkinson’s disease (PD) is characterized by progressive dopaminergic degeneration and maladaptive motor cortical plasticity. However, the cellular pathways underlying cortical surface activity in the primary motor cortex (M1) remain unclear, despite serving as a potential target for electrotherapy. We investigated the excitatory–inhibitory (E-I) balance and synaptic plasticity of superficial M1 circuits in a unilateral 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Using extracellular local field potential and whole-cell patch recordings from the contralateral and ipsilateral M1 hemispheres of hemi-parkinsonian rats, we observed a significantly elevated field excitatory postsynaptic potential (fEPSP) input–output function but unchanged intrinsic neuronal excitability in the M1 superficial layer. An altered relative contribution between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated transmission was reflected by a significantly increased AMPA/NMDA ratio. Markedly reduced inhibitory synaptic tone was also evidenced by the decreased amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), supporting an E-I imbalance favoring excitation in PD. Furthermore, group I metabotropic glutamate receptor (mGluR_1/5)-dependent long-term depression (LTD) was abolished in the ipsilateral PD hemisphere, whereas NMDAR-dependent LTD remained intact. In summary, dopamine depletion appears to enhance network excitation and disrupt mGluR_1/5-mediated control of M1 surface circuitry. Our findings identify altered cortical surface mGluR-dependent plasticity in the hemi-parkinsonian model; however, the relationship between these electrophysiological alterations and individual motor outcomes remains to be determined. Full article

Drosophila melanogaster shares approximately 75% of human disease-related genes and possesses sophisticated genetic toolkits, including GAL4/UAS, CRISPR-Cas9, and RNA interference (RNAi), making it a rapid, cost-effective, and genetically tractable in vivo platform for natural products (NPs) discovery. This review systematically summarizes the modeling strategies, pathological mechanisms, and therapeutic applications of Drosophila models for six major human diseases, including type 2 diabetes, nephrolithiasis, inflammatory bowel disease, cancer, Alzheimer’s disease, and Parkinson’s disease. Cross-disease analysis identifies five evolutionarily conserved signaling networks—IIS/PI3K/Akt/FOXO, JNK/JAK/STAT, Nrf2/Keap1, mTOR/TORC1, and IMD/Toll—as common molecular targets of bioactive NPs, providing a unified mechanistic framework for understanding their multi-target pharmacological activities and broad therapeutic potential. Critically, we propose a generalizable integrated stepwise pipeline: high-throughput fly screening of crude extracts, bioassay-guided isolation of active monomers, genetic mechanistic dissection via RNAi and mutant rescue, and layered validation in human cells and selective mammalian models. This pipeline addresses key challenges in NPs research, including the identification of bioactive constituents and mechanistic validation, while improving screening efficiency and translational potential. Overall, this review establishes a multi-disease-applicable framework linking disease modeling, conserved signaling mechanisms, and translational pharmacology, providing practical guidance for future mechanism-driven NP discovery and preclinical development using Drosophila. By leveraging Drosophila genetics to bridge evolutionary conservation and human pathology, this framework offers a powerful, paradigm-shifting strategy to accelerate mechanism-driven NP discovery and preclinical development. Full article