Search Results (7,549)

The increased activity of δ-aminolevulinic acid synthase-1 (ALAS1) leads to the accumulation of δ-aminolevulinic acid (ALA), which may reduce the iron(III) retention ability of ferritin, resulting in iron(III) overload. The accumulation of ALA occurs in the condition of attenuation of the heme negative feedback loop over ALAS1 activity in concert with the induction of ALAS1 expression. Attenuation of the heme negative feedback loop is maintained by elevated quantities of the heme catabolizing enzyme, heme oxygenase-1 (HO-1), which, in turn, may be induced by highly increased heme concentration. The upregulation of brain HO-1 occurs in patients with Alzheimer’s and Parkinson’s diseases. A mouse with overexpressed human HMOX1 is a model of schizophrenia with concurrent iron overload. HO-1 inhibitors reduce oxidative damage to whole cells and mitochondrial compartments of rat astrocytes transfected with the HMOX1 gene. Iron reduction within the heme prosthetic moiety of P450 cytochromes in microsomes is facilitated by NADPH-cytochrome P450 oxidoreductase (CPR), while adrenodoxin reductase performs this function in the mitochondria. In partial CPR-deficient conditions, the half-life of apocytochromes is prolonged while HO-1 is induced due to the elevated heme release from unreduced cytochromes. This study posits that, before being degraded by HO-1, the released hemin triggers the oligomerization of cytochromes, as well as other oxidative damages, by producing hydroperoxyl radicals from hydrogen peroxide produced in uncoupling reaction. After reaching a specific level, iron(III) overload may trigger the saturation of CPR, resulting in the development of neuropathologies. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the intracellular accumulation of alpha-synuclein (α-syn) aggregates. Historically, research has focused on neuronal mechanisms; however, growing evidence indicates that the progression of neurodegeneration is influenced by changes in the brain microenvironment, particularly through the dynamic interplay between microglia and the extracellular matrix (ECM). ECM in the central nervous system is an organized network of structural proteins, glycoproteins, and proteoglycans that encases neurons and glial cells, regulating processes such as synaptic stability, neural plasticity, and intercellular signaling. In PD, the aggregation of α-syn and neuronal damage induce sustained microglial activation, which can alter ECM structure. Activated microglia release proteases, including matrix metalloproteinases and cathepsins, which can degrade critical ECM components such as collagens, laminins, and proteoglycans. This remodeling can modify synaptic architecture, regulate cellular signaling, and disrupt neuron-glia interactions, fostering an environment conducive to dopaminergic degeneration. Furthermore, ECM remodeling and microglial activation exhibit regional variability within the brain. Regions notably prone to degeneration, such as the SNpc and striatum, display significant alterations in matrix organization and inflammatory activity, while other dopaminergic regions, including the ventral tegmental area, show increased resilience. We suggest that microglia-mediated ECM remodeling serves as a mechanistic link between neuroinflammation and neuronal susceptibility in PD. This review consolidates the existing knowledge on microglial modulation of ECM dynamics during neurodegeneration, explores regional differences in these processes, and evaluates their significance as possible treatment targets. Full article

A single-chain variable fragment (scFv) is an engineered antibody derivative that retains antigen-binding specificity while having a much smaller size than an antibody, improved tissue penetration, and enhanced versatility for genetic manipulation. When an scFv is fused with diverse protein payloads, multifunctional biologics can be created for targeted delivery and therapy. Over the past decade, scFv fusion proteins have gained significant traction in oncology, where they have been incorporated into immunotoxins, immunocytokines, bispecific antibodies, Chimeric Antigen Receptor (CAR)-T cells constructs, and immune cell engagers. In addition, advances in blood–brain barrier (BBB)-targeting strategies have enabled the exploration of scFv-based therapeutics for neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Despite promising preclinical and clinical outcomes, challenges such as structural instability, short half-life, immunogenicity, and manufacturing complexity remain. This review provides an in-depth and up-to-date overview of scFv fusion protein engineering and its therapeutic applications in cancer and neurodegenerative disorders. We also highlight the clinical translations and design principles of scFv fusion proteins. Full article

An important role of neuroinflammation in the pathogenesis of Parkinson’s disease (PD) has been proposed. Since some microRNAs (miRNAs), and miR-155 in particular, are involved in neuroinflammatory processes, a previous study reported an association between one of the most common single nucleotide variants (SNVs), rs767649, in the MIR155 gene, and risk for PD. The aim of the current study was to replicate this finding in a larger Spanish population case–control series. We analyzed genotype and allele frequencies of the MIR155 rs767649 SNV in a Spanish Caucasian cohort consisting of 459 PD patients and 460 age- and sex-matched healthy controls, using a TaqMan allelic discrimination assay specifically designed for rs767649. The genotype frequencies of the MIR155 rs767649, under codominant, dominant, recessive, and overdominant inheritance models, as well as allelic frequencies, showed no significant differences between PD patients and healthy controls. Likewise, the age at PD onset did not differ among the three MIR-155 rs767649 genotypes. These data did not identify a statistically significant association between MIR155 rs767649 variants and PD risk. However, the low frequency of the variant allele resulted in limited statistical power, and modest genetic effects cannot be excluded. Full article

Background/Objectives: Gastrointestinal dysmotility (GID) is a frequent non-motor manifestation of Parkinson’s disease (PD). However, its peripheral electrophysiological characteristics, as well as the underlying neural mechanisms within the brain–gut axis, remain insufficiently understood. This study aimed to delineate spatiotemporal abnormalities in gastrointestinal pacing activity in PD and to explore their associations with cerebral functional connectivity (FC). Methods: Multichannel electrogastroenterography (EGEG) recordings, including both preprandial and postprandial states from gastric (leads 1–4) and intestinal (leads 5–8) regions, were obtained from patients with PD and healthy controls (HCs), alongside resting-state functional MRI (rs-fMRI). The striatal–thalamic circuit was selected as the seed region for FC analysis. Between-group differences in EGEG-derived spatiotemporal metrics were assessed using analysis of covariance (ANCOVA), while FC differences were examined using two-sample t-tests. Partial correlation analyses were conducted to evaluate associations among neuroimaging measures, aberrant gastrointestinal electrophysiological indices, and clinical variables. Regional specificity of correlations was further tested by comparing dependent correlation coefficients. In addition, multivariate brain–gut connectivity was assessed using partial canonical correlation analysis (pCCA) with 1000 permutation tests. Results: Relative to HCs, PD patients exhibited a significant reduction in the proportion of normal slow waves in both gastric and intestinal regions during preprandial and postprandial states (pFDR < 0.05). FC analysis revealed increased connectivity between the left thalamus and right insula in PD, whereas interhemispheric connectivity of the caudate nuclei and putamina was significantly reduced. Additionally, FC between the left pallidum and left precentral gyrus was attenuated in the PD group. Partial correlation analysis demonstrated a positive association between postprandial normal slow-wave fraction and interhemispheric caudate connectivity (r = 0.63, pFDR = 0.047). Furthermore, left thalamus–right insula connectivity correlated with both total Non-Motor Symptoms Scale (NMSS) scores (r = 0.57, pFDR = 0.042) and gastrointestinal subscale scores (r = 0.63, pFDR = 0.037). At the multivariate level, pCCA revealed a strong association between lentiform nucleus connectivity and preprandial gastric slow-wave rhythms (canonical r = 0.892, p = 0.004). Conclusions: In PD, caudate nucleus FC shows a preferential association with gastric rather than intestinal electrophysiological activity. Multivariate analyses further demonstrate a significant network-level association between lentiform nucleus connectivity and baseline gastric pacing rhythms, extending regional findings to a broader network interaction. Together, these results provide multimodal correlational evidence reflecting parallel central and peripheral alterations in PD, highlighting synchronized alterations in central networks and peripheral gastrointestinal rhythmicity. Full article

Genetic mutations, altered RNA regulation, and protein aggregation are the main hallmarks of Parkinson’s disease (PD), a neurodegenerative disorder. Investigation into the molecular basis of the disease revealed that post-transcriptional regulation, specifically RNA processing, contributes to neuronal vulnerability in PD. Alterations in alternative splicing affecting genes involved in neuronal function and cellular homeostasis have been reported in PD, including SNCA, LRRK2, MAPT, PRKN, and BIN1. These alterations impact central neuronal pathways, including cytoskeletal maintenance, mitochondrial function, synaptic activity, oxidative stress, and intracellular trafficking. This review aims to provide an overview of alternative splicing in key PD gene transcripts, with a focus on their roles in pathogenesis and disease progression. Emerging data suggest that dysregulation of RNA binding proteins (RBPs) may influence RNA processing in PD. We will examine current evidence on the RNA regulatory networks in PD, highlighting the role of transcript isoforms and RBPs in neuronal dysfunction. Finally, we will discuss emerging experimental models such as 3D-brain organoids that offer new opportunities to investigate splicing regulation. Full article

Background: Parkinson’s disease (PD) is characterized by a complex interplay of dopaminergic degeneration, glial activation, and lipid metabolic dysregulation. However, accurately describing how natural product interventions remodel these pathologies across distinct brain regions and cellular microenvironments remains a critical challenge. Methods: We established an integrated multi-omics framework to decode the neuroprotective mechanisms of solanesol (Sol) in an MPTP-induced PD mouse model. We combined single-cell eQTL-based Mendelian randomization (scMR), transcriptomic localization, and virtual knockout analyses to prioritize cell-type-specific regulatory nodes across neuronal, glial, and vascular populations, avoiding the limitations of traditional bulk targeting. In vivo behavioral assays were conducted, alongside orthogonal validation via airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) and gene–metabolite co-enrichment analysis, to map regional metabolic networks and structural spatial reprogramming. Results: Computational prioritization highlighted cell-type-specific regulatory nodes including PRKCB, PRKCE, PDGFRB, and FABP3/5. In vivo, Sol attenuated motor and cognitive deficits and largely restored the highly compartmentalized spatial distributions of striatal dopamine, L-DOPA, and acetylcholine. Crucially, AFADESI-MSI and co-enrichment analysis revealed that Sol specifically reversed MPTP-induced spatial disruptions by rescuing key neuromodulatory metabolites—including cervonoyl ethanolamide, phosphatidylcholine species, taurine, and NADHX—which were tightly coupled to sphingolipid signaling, fatty-acid transport, mitochondrial translation, and cell-adhesion pathways. Conclusions: Sol ameliorates PD-like pathology not through a singular target, but by choreographing a spatially and cellularly compartmentalized restoration of lipid–inflammatory homeostasis. Furthermore, our integrated single-cell and spatial metabolomic blueprint sets a new methodological paradigm for elucidating the precise execution programs of natural neurotherapeutics. Full article

Background: Patient stratification in Parkinson’s disease (PD) is constrained by clinical heterogeneity, longitudinal attrition, and the absence of frameworks that compare subtyping configurations under matched feature families, cluster numbers, and modelling assumptions. Existing approaches rarely validate recovered partitions with quantitative imaging biomarkers under multiple-testing control or with a generative model whose dispersion diagnostics are transparently reported. Methods: We develop a fully traceable multi-source data fusion pipeline for the Parkinson’s Progression Markers Initiative (PPMI) cohort, combining: (i) clinical subtype discovery via a z-score SuStaIn approximation explored across a 96-configuration sensitivity grid; (ii) external validation of the recovered subtypes against longitudinal DaTscan and R2* MRI biomarkers; and (iii) conditional trajectory generation via a Real NVP normalising flow. Methodology selection is performed on the $n=798$ longitudinally complete subset using BIC, longitudinal stability, and imaging validation as independent criteria. Results: The two-subtype Subscores partition (slow-/rapid-progression, $\mathrm{BIC}=-\mathrm{531,724}$, $n=798$) achieves the best information criterion, the highest longitudinal retention (80-87% across visit pairs), and the strongest imaging validation. DaTscan striatal binding ratios differentiate the two subtypes under Benjamini–Hochberg correction at V06 ($q<0.001$ for right caudate and bilateral putamen mean) and V10. R2* substantia nigra markers do not reach significance ($n=14$–51, underpowered; reported as exploratory). The conditional normalising flow converges stably (epoch 8 checkpoint, ${\mathrm{NLL}}_{\mathrm{val}}=42.41$) with near-correct dispersion (${\sigma }_{\mathrm{gen}}/{\sigma }_{\mathrm{real}} \mathrm{mean}=1.14$). Conclusions: A two-subtype clinical partition, validated longitudinally against DaTscan biomarkers and supported by a converged conditional generative model, provides a defensible imaging-validated stratification framework for PD; the sensitivity grid clarifies the configuration space and strengthens the case for the retained methodology. Replication on independent cohorts (AMP-PD, PDBP, OPDC) is required before clinical translation. Full article

Virtual Reality is an interactive technology that creates immersive, computer-generated three-dimensional environments for therapeutic and rehabilitative purposes. In neurorehabilitation, it has been increasingly adopted to support motor, cognitive, emotional, and functional recovery via task-oriented, multisensory, and feedback-driven interventions. Originally developed for exposure-based therapies, its applications have expanded to neurological conditions such as stroke, traumatic brain injury, Parkinson’s disease, multiple sclerosis, spinal cord injury, and chronic pain. Its therapeutic rationale is thought to rely on mechanisms including neuroplasticity, multisensory integration, motor learning, embodiment, and adaptive feedback. Despite the fact that standardized clinical protocols are still evolving, VR is considered a complement to conventional neurorehabilitation, with advances in artificial intelligence and wearable technologies expected to further enhance its clinical applications. Full article

Background/Objectives: Dilated cardiomyopathy (DCM) is a genetically heterogeneous myocardial disorder. Emerging evidence suggests that some genes implicated in DCM may also be associated with neurological disorders, supporting the concept of genetic pleiotropy. This study explored the intersection between cardiac and neurological genetics, with the aim of identifying candidate genes that may contribute to shared pathogenic pathways linking these clinically distinct conditions. Methods: We performed exome sequencing in 149 patients with echocardiographically confirmed DCM and subsequently applied an in silico filter to a predefined list of 211 genes associated with inherited cardiomyopathies. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Genes with validated evidence for DCM according to the Clinical Genome Resource (ClinGen) were further investigated through the Human Gene Mutation Database (HGMD) and a focused literature review to identify reported associations with neurological disorders. Results: Genetic variants in DCM-associated genes were identified in 105 patients. Overall, 137 variants were detected, including pathogenic variants and variants of uncertain significance. The most frequently involved genes were TTN, FLNC, and MYH6. Several DCM-associated genes also showed reported associations with neurological disorders, including autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, epilepsy, and schizophrenia. Among them, TTN, FLNC, RYR2, and SCN5A displayed the broadest overlap between cardiac and neurological phenotypes. Conclusions: These descriptive findings show that variants were most frequently observed in TTN, FLNC, and MYH6 and that several genes included in the ClinGen DCM curation framework have also been independently reported in neurological disorders. Because most identified variants were VUS and no control group or systematic neurological phenotyping was available, the findings indicate gene-level co-annotation only and do not establish variant enrichment, shared pathogenic mechanisms, or clinical overlap. Full article

Background: The Braak hypothesis proposes that α-synuclein (α-syn) pathology may originate in the gastrointestinal tract and propagate to the central nervous system along the gut–brain axis; however, the precise propagation routes and the factors influencing this process remain controversial. Methods: A gut-originating Parkinson’s disease model was established by injecting α-syn preformed fibrils (PFF) into the duodenal muscularis of C57BL/6J and A53T transgenic mice. Phosphorylated α-synuclein (p-α-syn) pathology, motor behavior, and gut microbiota were assessed, with truncal vagotomy included to evaluate its association with gut-to-brain propagation. Results: In C57BL/6J mice, at 4 months post-injection, p-α-syn deposition was observed in both the duodenal muscular layer and the striatum, accompanied by gut microbiota alterations and motor behavioral deficits. Truncal vagotomy was associated with reduced p-α-syn levels in the brain and alterations in the gut microbiota. In A53T transgenic mice, p-α-syn pathology and neurodegenerative changes were also observed following α-syn PFF injection, though the lack of a genetically matched wild-type control precludes definitive attribution of these phenotypes solely to the A53T transgene. Conclusions: These results align with the Braak hypothesis, showing that gut-derived p-α-syn pathology and associated functional impairments are intimately linked to vagal pathways during their propagation to the brain. Additionally, this gut-origin PD mouse model may serve as a useful tool for future mechanistic investigations. Full article

Dietary patterns increasingly influence research on neurodegenerative diseases, with attention shifting from isolated nutrients to integrative nutritional models. The Amazonian Diet, a biodiversity-based dietary pattern rich in native fruits, seeds, freshwater fish, and cassava-derived foods, is naturally enriched in bioactive compounds including polyphenols, anthocyanins, carotenoids, methylxanthines, selenium, vitamins, and unsaturated fatty acids. This review aimed to investigate the potential relevance of key foods derived from the Amazonian Diet to Parkinson’s disease (PD) by integrating compositional nutritional analysis, multivariate analytical approaches, and mechanistic evidence synthesis. In Stage 1, the composition of 36 Amazonian foods was analyzed using TBCA and FAO data, followed by hierarchical clustering analysis (Ward’s linkage, Euclidean distance). Distinct compositional patterns were identified, highlighting foods with high bioactive diversity, relevant lipid composition, and dietary fiber. In Stage 2, an integrative literature review (PubMed/MEDLINE, SciELO) of in vitro, in vivo, observational, and clinical studies suggested that açaí berry, guaraná, cocoa/cacao, camu-camu, and Brazil nuts contain nutrients and bioactive compounds that intersect with biological pathways implicated in PD, including oxidative stress, mitochondrial dysfunction, and neuroinflammation. However, this review does not evaluate the effects of the Amazonian Diet on PD incidence, progression, symptoms, levodopa response, or biomarkers. Full article

Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with a well- documented prodromal phase during which non-motor symptoms appear years before motor onset. Seborrheic dermatitis (SD) is a chronic inflammatory skin disease that is significantly more prevalent in PD patients than in the general population. The biological mechanisms underlying this association have not been integrated into a single framework. Objectives: This narrative review aims to synthesise the available evidence on the molecular, genetic, and pathophysiological mechanisms linking SD and PD. Methods: A literature search was conducted across PubMed/MEDLINE, Scopus and ScienceDirect, supplemented by manual searches in OMIM and GeneCards. Results: Four major biological links between SD and PD have been proposed. First, alpha-synuclein deposits are detectable in cutaneous nerve fibres and autonomic fibres innervating sebaceous glands in PD patients and their pattern has been associated with disease subtype and progression. Second, dysfunction in ceramide and sphingolipid metabolism, associated with variants in GBA1, LRRK2, and ZNF750, has been linked to impaired lysosomal function and skin barrier integrity in both brain and skin tissue. Third, Malassezia, a commonly associated organism and possible trigger in susceptible hosts, produces metabolites that activate neuroinflammatory pathways relevant to PD and PD patients show altered Malassezia species composition on their skin. Fourth, NLRP3 inflammasome activation, which can be triggered by ceramide accumulation and fungal metabolites, has been proposed as a shared inflammatory mechanism that may operate in both keratinocytes and dopaminergic neurons. Conclusions: SD and PD appear to share overlapping genetic, lipidomic, microbial, and neuroinflammatory features. These associations are consistent with, but do not yet prove, a common pathological basis rather than a coincidental one. SD may therefore represent a potential prodromal feature or risk marker of PD. Future research should examine whether targeted intervention in high-risk SD patients can delay or modify PD onset. Full article

Objectives: Accurate severity classification is important for sensor-based assessment of Parkinson’s disease, but overlap between adjacent stages and class imbalance can reduce model robustness. This study aimed to develop and evaluate a dual-task gait fusion framework that integrates signals collected during self-selected walking and walking with turning. Methods: The primary cohort comprised 87 participants with Parkinson’s disease across mild, mild-to-moderate, and moderate stages. Task-specific temporal representations were learned from the two gait conditions, concatenated and optimized using delayed class re-weighting. Performance was evaluated using subject-level stratified five-fold cross-validation with five random seeds. Generalizability was further assessed using an independent PhysioNet cohort of 93 participants with Parkinson’s disease. Results: The proposed method achieved an accuracy of 90.23 ± 1.27, balanced accuracy of 89.61 ± 1.13, macro F1-score of 89.10 ± 1.35, and probability-based macro AUC of 94.43 ± 1.42 on WearGait-PD. Confusion matrix and ablation analyses indicated balanced class-level performance and complementary contributions from dual-task fusion and delayed re-weighting. On the external PhysioNet cohort, accuracy, balanced accuracy, macro F1-score, and macro AUC were 84.34 ± 1.82, 82.13 ± 1.92, 81.68 ± 1.98, and 88.93 ± 2.14, respectively. Conclusions: Integrating turning-related gait information with self-selected walking signals improved wearable sensor-based severity classification and showed cross-dataset robustness, although validation in larger cohorts with complete severity stage coverage remains necessary. Full article