Search Results (7,888)

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

Background: Progressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy in which neurodegeneration may be accompanied by neuroinflammatory and peripheral immune alterations. Whether peripheral inflammatory activity reflects structural degeneration within vulnerable brain networks remains unclear. Methods: This retrospective case–control study included 12 patients with PSP and 12 patients with Parkinson’s disease (PD). Automated volumetric analysis of 3-Tesla MRI was performed using volBrain 2.0. Blood-derived inflammatory indices included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammation response index (SIRI), and red blood cell distribution with coefficient of variation (RDW-CV). Results: Patients with PSP showed significantly lower normalized superior frontal gyrus and pallidal volumes than patients with PD. Within the PSP group, higher values of selected blood-derived inflammatory indices were associated with lower frontal network volumes. After adjustment for age, MLR was inversely associated with the composite Frontal Network Score (partial r = −0.7333, p = 0.0067, FDR q = 0.020). The strongest regional association was observed between SIRI and medial frontal cortex volume (rho = −0.748, p = 0.0051); however, regional associations did not remain significant after FDR correction. Conclusions: Peripheral inflammatory markers were associated with MRI-derived measures of frontal network degeneration in PSP. The association between MLR and the composite Frontal Network Score supports a link between systemic immune alterations and network-level neurodegeneration in PSP. Full article

Parkinson’s disease (PD) is associated with motor impairment and altered cortical dynamics. Although resting-state electroencephalography (EEG) has been widely studied for PD classification, walking EEG remains comparatively underexplored despite its relevance to gait dysfunction. This study developed an EEG-only, leakage-free framework for participant-level classification of PD and healthy controls (HCs) using resting- and walking-state EEG data from the OpenNeuro ds007526 dataset. Following selection, preprocessing, and quality control, 132 participants were retained, including 109 individuals with PD and 23 HCs. EEG recordings were resampled to 128 Hz, filtered between 0.5 and 40 Hz, screened for artifacts, harmonized across conditions, and segmented into overlapping 6 s windows. Classical machine-learning (ML) models used participant-level engineered features, whereas deep-learning (DL) models classified pooled resting-state and walking windows. Extra Trees achieved the highest balanced accuracy (0.71) among the ML, while ShallowConvNet-Lite was the strongest standard DL baseline (0.82). The proposed NeuroAtten-PD model achieved an accuracy of 0.86, a balanced accuracy of 0.84, an F1-score of 0.91, an ROC-AUC of 0.90, and a sensitivity of 0.88. After Holm correction, participant-level paired comparisons indicated significant differences from DeepConvNet-Lite and EEGNet-Lite. These findings demonstrate the feasibility of participant-level PD classification using a pooled collection of resting-state and walking EEG windows. With validation in larger, independent, and more balanced clinical cohorts, the proposed framework could support objective EEG-based decision support and provide a foundation for portable or wearable systems for longitudinal monitoring of PD-related cortical changes in clinical and home-based settings. Full article

Parkinson’s disease (PD) is associated with alterations in gait symmetry and plantar loading that can be examined using vertical ground reaction force (VGRF) recordings. This study presents a confidence-stratified, physiology-anchored multiple-instance learning framework with concept-bottleneck-inspired pathways (implementation identifier: DRO-PAS-MIL-CBM; hereafter, PAS-MIL) for retrospective session-level PD-versus-control classification. Each gait session is represented as a bag of temporal windows. Eight predefined bilateral signal descriptors are combined with eight learned latent temporal dimensions, aggregated through attention-based pooling, and processed by concept-guided, prototype, anchor-only, and static-feature expert pathways. The evaluation used five-fold person-grouped cross-validation on 306 sessions from 165 participants in the PhysioNet Gait in Parkinson’s Disease database.Inner person-grouped out-of-fold ExtraTrees probabilities were used to construct the confidence strata and distillation targets. PAS-MIL achieved a pooled session-level area under the receiver operating characteristic curve of 0.771, average precision of 0.890, and a mean fold AUC of $0.826\pm 0.041$. Relevance analysis identified C05 (asymmetry variability) and C08 (bilateral change mismatch) as the highest-weighted predefined physiological anchor descriptors. Protocol-stratified sensitivity analysis showed variation across the three source sub-studies, with AUCs ranging from 0.740 to 0.790. Probability calibration remained suboptimal after temperature scaling (mean per-fold ECE, $0.291\pm 0.042$). The results demonstrate the feasibility of integrating physiology-informed descriptors, temporal representation learning, and session-level aggregation. The study is a retrospective proof of concept and does not establish external robustness or clinical deployment readiness. Full article

Glutathione is an abundant intracellular low-molecular-weight thiol that contributes importantly to cellular redox homeostasis. Besides its well-established role in the antioxidant defense of the cell, glutathione regulates mitochondrial function, metabolism of toxicants, protein thiol oxidation/reduction, redox signaling, and immunity. Disturbances in glutathione metabolism have been shown to play a role in various diseases; however, it has become clear that changes in glutathione metabolism are a part of a complex, multifactorial process. In this review, we summarize current knowledge of the molecular mechanisms governing glutathione synthesis, recycling, compartmentalization, and biological functions, with particular emphasis on redox signaling, the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway, and reversible protein S-glutathionylation. We further examine how disturbances in glutathione homeostasis interact with mitochondrial dysfunction, chronic inflammation, metabolic stress, and impaired cellular signaling in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, Wilson’s disease, type 2 diabetes, and nonalcoholic fatty liver disease. We also evaluate current translational interventions targeting restoration of glutathione balance through glutathione supplementation, precursor supplementation, pharmacological modulation of endogenous antioxidant mechanisms, dietary interventions, and changes in lifestyle. Despite the fact that many interventions have been promising at the mechanistic and experimental level, there are still insufficient clinical data because of the problems associated with glutathione availability, tissue specificity, disease variability, and a lack of sufficiently powered clinical trials. The conclusion of this review is that glutathione should not be viewed as a universal therapeutic target; instead, glutathione should be perceived as an important factor contributing to cellular resilience and able to help other disease-specific interventions. Future progress in glutathione-based interventions will likely depend on integrating redox biomarkers, patient stratification, and precision medicine strategies to identify individuals most likely to benefit from targeted modulation of glutathione homeostasis. Full article