Search Results (1,514)

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. While most cases are sporadic, around 10% are familial. Recent genetic studies show that many apparently isolated cases carry pathogenic mutations, highlighting the importance of penetrance, the probability that a causal mutation manifests clinically. This review focuses on mutation penetrance in ALS (C9orf72, SOD1, TARDBP, FUS genes), its variability across genes, age, and environmental or genetic modifiers, and its implications for genetic counseling. Identification of pathogenic mutations informs the monitoring of relatives and, in some cases, gives access to targeted therapies or clinical trials. Counseling of asymptomatic relatives must consider incomplete penetrance, which can lead to delayed or absent disease manifestation. ALS exists on a clinical and genetic continuum including related disorders, such as frontotemporal dementia, further influencing risk interpretation. Advances in panel, whole-exome and whole-genome sequencing refine our understanding of penetrance and enable precise diagnostics, and potential tailored therapies. Understanding penetrance is therefore essential to translate mutation discovery into informed clinical decisions and genetic counseling in ALS. Full article

At present, there is still a lack of effective treatments to slow the progression of Parkinson’s disease. Naturally derived active substances, valued for their safety and multi-target potential, have become an important direction in anti-PD drug development, with marine organisms representing a valuable source of bioactive peptides. This study aimed to isolate and identify anti-PD peptides from Rapana venosa protein hydrolysates. Through bioactivity-guided screening combined with an MPTP-induced zebrafish PD model, three novel active peptides—KSTELLI, FLVKLPMFM, and SDSLSEILIS—were successfully identified. The study showed that these peptides significantly alleviated dopaminergic neuron loss, improved the cerebral vascular system, restored motor and sensory function, and alleviated oxidative stress. Molecular docking confirmed their stable binding to key PD targets (DDC, α-synuclein, and MAO-B). Further transcriptomic and gene expression analyses revealed that their neuroprotective effects involve the regulation of pathways related to metabolism, oxidative stress, inflammation, and apoptosis, with the three peptides exhibiting distinct mechanistic emphases. The research demonstrates that these marine-derived peptides exert neuroprotective effects through a synergistic multi-target mechanism, laying a foundation for the development of novel lead compounds against Parkinson’s disease. Full article

Background: This pilot study examined whether oxidative–nitrosative stress is associated with clinical status in amyotrophic lateral sclerosis (ALS). We analyzed associations between plasma markers of oxidative–nitrosative imbalance and ALSFRS–R, disease duration, survival, and routine biochemical parameters. Methods: Twenty-nine ALS patients fulfilling the Gold Coast diagnostic criteria were enrolled. Plasma levels of 3-nitrotyrosine (3–NT), 8-oxo-2′-deoxyguanosine (8–oxodG), malondialdehyde (MDA), glutathione (GSH), non-protein thiols (NP–SH), and non-protein disulfides (NP–SS–NP), as well as creatinine, urea, uric acid and BMI, were measured. Associations with ALSFRS–R and disease duration were evaluated using non-parametric correlation analyses and second-order polynomial regression (adjusted R²), while survival was explored using Kaplan–Meier analysis and multivariable Cox regression. Given the modest sample, we considered statistical power and applied Benjamini–Hochberg false discovery rate (FDR) correction within marker families. Results: At the uncorrected significance level, 3–NT showed a positive correlation with ALSFRS–R and a negative correlation with disease duration, and NP–SH correlated negatively with disease duration; however, these associations did not remain significant after FDR correction (FDR-adjusted p ≥ 0.099). Other oxidative–nitrosative markers and biochemical parameters showed no robust relationships with clinical measures. In Cox models, 3–NT was not significantly associated with survival (HR 3.44 per 1 nM, 95% CI 0.25–47.97, p = 0.358), whereas older age predicted higher mortality (HR 1.05 per year, 95% CI 1.00–1.10, p = 0.036). Conclusions: 3–NT and NP–SH exhibited the strongest trends among the investigated markers, but their clinical associations in this small cross-sectional cohort remain exploratory and require confirmation in larger longitudinal studies. Full article

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection and is frequently complicated by sepsis-associated encephalopathy (SAE), which contributes to long-term cognitive and neuropsychiatric sequelae. Despite advances in critical care, effective targeted therapies for SAE remain limited. Aquaporin-4 (AQP4), the predominant astrocytic water channel, plays a central role in cerebral water homeostasis, neuroinflammatory signaling, and blood–brain barrier integrity, suggesting its potential involvement in sepsis-induced cerebral dysfunction and neurorepair processes. Polymicrobial sepsis was induced in C57BL/6J mice using the cecal ligation and puncture (CLP) model. AQP4 activity was pharmacologically modulated through either inhibition or facilitation following sepsis induction. Disease severity was assessed using physiological parameters and a modified murine sepsis score. Neurological outcomes were evaluated through standardized behavioral tests assessing locomotor activity, motor coordination, cognitive performance, and depressive-like behavior. Neuroinflammatory and neuronal changes were examined by immunohistochemical analyses of microglial activation (Iba1), astroglial reactivity (GFAP), neuronal integrity (NeuN), and AQP4 expression. Compared with AQP4 facilitation, pharmacological inhibition of AQP4 was associated with a more favorable clinical recovery profile, reflected by lower sepsis severity scores and a more favorable body weight trajectory during the recovery phase. Behavioral analyses demonstrated preserved cognitive function, enhanced motor coordination, and reduced depressive-like behavior in AQP4 inhibitor-treated mice compared with animals receiving AQP4 facilitation. At the histological level, the inhibitor-treated group showed lower microglial and astroglial activation and better preservation of neuronal markers than the facilitator-treated group, whereas AQP4 facilitation exacerbated neuroinflammatory responses and neuronal alterations. These findings highlight a dual, context-dependent role of AQP4 in sepsis-associated cerebral dysfunction. These findings suggest that AQP4 modulation influences sepsis-associated cerebral dysfunction in a context-dependent manner. Within our experimental design, AQP4 facilitation was associated with worse outcomes, whereas AQP4 inhibition was associated with a comparatively more favorable neurobehavioral and histological profile. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily caused by the degeneration of dopamine-producing neurons in the substantia nigra, leading to characteristic motor symptoms such as tremors, rigidity, and bradykinesia, as well as non-motor manifestations including depression, sleep disturbances, and speech impairments. Among these symptoms, speech abnormalities affect approximately 90% of individuals with PD, making acoustic analysis a promising non-invasive cue for early detection. However, subtle speech variations are often imperceptible to the human ear, and speech-only analysis may overlook complementary visual manifestations, such as hypomimia—reduced facial expressivity commonly observed in PD patients. To address these limitations, we propose Parkinson’s Detection via Attentional Fusion Network (PDAF-Net), a novel multimodal deep learning framework for early PD detection that jointly models acoustic and facial dynamic features in a binary classification setting. The proposed architecture consists of a Dual-Stream Feature Encoder (DSFE), with an audio branch based on a one-dimensional convolutional neural network (1D-CNN) and bidirectional long short-term memory (BiLSTM), and a visual branch built upon a two-dimensional convolutional neural network (2D-CNN) and a Transformer encoder. Multimodal integration is achieved through a Cross-Attention-guided Attentional Feature Fusion (CA-AFF) module, which explicitly models bidirectional cross-modal interactions and performs adaptive feature recalibration via an iterative attentional fusion mechanism. We conducted experiments on a self-collected Chinese multimodal dataset comprising 100 PD patients and 100 healthy controls. Although the data are balanced at the subject level, sliding-window segmentation introduces sample-level imbalance; to address this issue, a class-balanced focal loss is employed. Model performance was evaluated using subject-wise five-fold cross-validation. The results demonstrate that PDAF-Net consistently outperforms unimodal baselines across multiple evaluation metrics, achieving an accuracy of 89.3%, an F1-score of 0.884, and an AUC of 0.916. These findings highlight the effectiveness of explicit cross-modal interaction modeling and adaptive feature fusion for improving automated early PD screening in real-world clinical settings. Full article

Background: The absence of disease-modifying treatments for Parkinson’s disease (PD)—a neurodegenerative condition with escalating global incidence—represents a critical unmet medical need. Traditionally utilized for both dietary consumption and medicinal preparations, the fruit derived from Rosa roxburghii Tratt demonstrates a remarkably rich profile of biologically active compounds, with flavonoids, triterpenoids, and organic acids representing the predominant classes. Experimental evidence indicates that these compounds elicit robust antioxidative, anti-inflammatory, and neuroprotective effects, making them promising candidates for neurodegenerative disease modulation. This study aimed to systematically evaluate the neuroprotective effects of Rosa roxburghii Tratt juice concentrate powder (RRJCP) across the preventive, interventional, and therapeutic stages of PD and to elucidate its underlying molecular mechanisms. Methods: Rosa roxburghii Tratt juice was subjected to rotary evaporation concentration and vacuum freeze-drying to obtain the juice concentrate powder. C57BL/6 mice were randomly assigned to three main groups (prevention, intervention, and treatment), each containing subgroups including a normal control, an MPTP model group, low-, medium-, and high-dose RRCJP groups (50, 100, and 200 mg/kg), and a positive control Madopar group, totaling 18 subgroups. A chronic MPTP-induced PD mouse model was established. Motor function was assessed via the open field test, pole test, and wire hang test. Substantia nigra neuronal morphology was examined by hematoxylin and eosin staining. The area of tyrosine hydroxylase (TH)-positive regions was measured by immunohistochemistry. The levels of oxidative stress indicators in serum were measured using biochemical kits. Network pharmacology was employed to predict core targets, and the expression of PI3K/AKT pathway and apoptosis-related proteins was determined by Western blotting. Results: Compared with the MPTP model group, RRCJP (200 mg/kg) significantly increased the total distance traveled in the open field, shortened the pole climbing time, and improved the wire hang score. It attenuated the morphological disorganization and nuclear pyknosis of substantia nigra neurons, increased the TH-positive area and TH protein expression, reduced serum MDA content, and elevated the activities of SOD and GSH-Px. Network pharmacology analysis indicated that the PI3K/AKT signaling pathway was among the core targets. Western blotting results further showed that the juice concentrate powder upregulated the expression of p-PI3K, p-AKT, and Bcl-2, while downregulating Bax and Cleaved Caspase-3 levels, which was consistent with the network pharmacology prediction. Conclusions: RRCJP exerts neuroprotective effects across the preventive, interventional, and therapeutic stages in PD model mice, the mechanisms of which may be associated with activation of the PI3K/AKT signaling pathway, attenuation of oxidative stress, and inhibition of neuronal apoptosis. Full article

Neurodegenerative disorders, including Parkinson’s disease (PD), are largely treated with symptomatic therapies, underscoring the need for strategies that target underlying disease mechanisms. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R), a class B G protein-coupled receptor best known for metabolic regulation, have attracted interest due to the increasing evidence of central nervous system (CNS) actions. This review synthesises mechanistic, preclinical, and clinical evidence examining GLP-1R signalling in PD and related neurodegenerative contexts. We integrate findings from cellular and animal models with early-phase clinical studies of GLP-1 receptor agonists (GLP-1RAs). Across experimental systems, GLP-1R activation engages conserved intracellular pathways—cAMP/PKA, PI3K/Akt, and ERK—that regulate mitochondrial function, oxidative stress, autophagy-lysosomal dynamics, and inflammatory signalling. In PD-relevant models, these pathways intersect with key pathogenic features, including α-synuclein accumulation, dopaminergic neuron vulnerability, and glial reactivity. Clinical studies to date demonstrate acceptable safety and tolerability, alongside biomarker evidence of central pathway engagement and variable effects on motor and non-motor outcomes. However, uncertainties remain regarding CNS target engagement, peripheral versus CNS mechanisms, and disease-stage dependence. Overall, the current evidence positions GLP-1R signalling as a biologically plausible therapeutic pathway in PD that warrants further mechanistic clarification and rigorous evaluation in ongoing and future clinical trials. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology. Full article

The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER)-resident protein enriched at the mitochondria-associated ER membranes (MAMs) that supports ER homeostasis, preserves mitochondrial function, and enhances cell survival under stress. Disruptions of MAM integrity and prolonged ER stress are well-recognized pathological features of amyotrophic lateral sclerosis (ALS), contributing to motor neuron dysfunction and degeneration. In this study, we evaluated the protective effects of pridopidine, a highly selective and potent S1R agonist currently in clinical development for Huntington’s disease (HD) and ALS, using neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) from a patient with sporadic ALS. Exposure of ALS NPCs to the ER stressor tunicamycin increased the ER stress markers binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP), disrupted mitochondrial membrane potential, upregulated expression of the mitochondrial apoptotic marker, BAX, increased caspase-3 activation, and reduced cell viability. Pridopidine significantly attenuated tunicamycin-induced BiP and CHOP expression in a biphasic, dose-dependent manner (with maximal efficacy at 1 µM), consistent with the typical pharmacology of S1R agonists. Pridopidine restored mitochondrial membrane potential, reduced mitochondrial apoptotic signaling, shown by decreased BAX expression and caspase-3 activation, and improved survival of ALS-NPCs under ER stress. Co-treatment with the selective S1R antagonist, NE-100, attenuated these effects, supporting an S1R-mediated mechanism of action for pridopidine. Together, these results demonstrate that S1R activation by pridopidine mitigates ER-stress-induced mitochondrial dysfunction and cell loss in ALS-NPCs, resulting in enhanced survival of NPCs supporting the therapeutic potential of pridopidine in ALS. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder that poses a substantial threat to global human health. Yam (Dioscorea opposita Thunb.) is a traditional medicinal and edible plant that has long been used in Asia, Africa, and the Caribbean. Its major bioactive components, such as dioscin and polysaccharides, have been reported to exhibit neuroprotective effects; however, the impact of dietary yam on PD progression remains to be elucidated. Therefore, we sought to evaluate its neuroprotective potential and the underlying mechanisms in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced PD mice. Methods: Mice received six-week dietary yam supplementation. Behavioral, histological, and neurochemical analyses were performed to assess motor function, dopaminergic neuron integrity, and dopamine levels. Gut microbiota and metabolic profiles were analyzed using 16S rRNA gene sequencing and non-targeted metabolomics. Transcriptomic sequencing and Western blot analysis of the substantia nigra pars compacta (SNc) were conducted to investigate molecular mechanisms, and integrative multi-omics analysis was applied to explore microbiota–metabolite–host interactions. Results: Yam supplementation improved motor function, preserved nigrostriatal dopaminergic neurons, and restored striatal dopamine levels in PD mice. Notably, yam was associated with the maintenance of intestinal homeostasis by strengthening barrier integrity and enriching beneficial taxa, including Ileibacterium, Lachnospiraceae NK4A136 group, and Blautia. Consistently, yam also elevated neuroprotective purines and amino acids, including inosine, xanthine, and succinic acid. At the molecular level, yam treatment modulated mitochondrial oxidative phosphorylation by increasing PGC-1α and COX7c expression, and reduced inflammasome-related neuroinflammatory signaling. Integrative modeling showed significant associations between yam-modulated genes and PD-related indices with microbiota and metabolites. Conclusions: These findings suggest that yam may represent a potential dietary strategy for alleviating PD-related neurodegeneration by modulating the microbiota–gut–brain axis. Full article

Motor neuron diseases (MNDs) encompass a clinically heterogeneous group of neurodegenerative conditions with varying impact on dexterity, mobility, decision making, respiratory and bulbar dysfunction. While consensus best-practice recommendations exist for genetic screening, diagnostic work-up, pharmacological and respiratory management, disease-specific facets of driving safety, assessment approaches and intervention strategies to support patients for safe driving have not been comprehensively reviewed. MNDs have unique, phenotype-specific clinical features, which are distinct form other neuromuscular conditions which necessitate a careful and systematic approach to evaluate driving safety. While MNDs are primarily associated with progressive motor impairment, extrapyramidal, cerebellar, cognitive, behavioural, and respiratory manifestations of the disease also affect driving safety and necessitate comprehensive driving assessments and individualised strategies to enable patients to continue to drive. The majority of existing papers focus on amyotrophic lateral sclerosis, and low-incidence MND phenotypes, such as PLS, SBMA, PPS, are glaringly understudied from a driving safety perspective despite the relatively slower progression of these conditions. Beyond the review of specific aspects of driving in MNDs, the main objective of this review paper is to raise awareness of non-motor aspects of MNDs with regard to driving safety and to explore viable strategies to support patients to maintain their independence. Despite the considerable differences in driving regulations around the globe, there are core, disease-specific aspects of MND which are universal. The careful consideration of these clinical factors, comprehensive domain-by-domain assessments, and the implementation of practical, individualised adaptations may enable patients to continue driving safely, maintain their independence and enhance their quality of life. Full article

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of motor neurons and skeletal muscle. Gene expression analysis of the spinal cord and gastrocnemius of the SOD1-G93A ALS mouse model revealed a strong increase in inflammatory pathways and, specifically in the ALS gastrocnemius, a decrease in mitochondrial transcription and an increase in ribosomal protein expression. Treatment of ALS mice with the polyamine spermidine (SPD), a promising molecule in combating neurodegeneration and muscle atrophy, is able to partially restore the expression of more than four thousand genes in gastrocnemius tissue, including the mitochondrial regulator Pgc1α, as well as all the mitochondrial encoded genes and a large class of ribosomal proteins. SPD enhanced mitochondrial bioenergetics, as evidenced by Seahorse experiments, and delayed muscle weakness in vivo, as shown by grip strength records. These findings suggest that SPD can act as a potential supplement in the therapeutic strategy for ALS, offering a foundation for further research to improve patient outcomes. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Lipid metabolism, especially phospholipids, has been reported to be altered in PD. The purpose of this study is to investigate the temporal expression and spatial distribution of phospholipids in the motor cortex and striatum at different time points of PD using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model. Mice were injected with saline (NSS) or MPTP at two different time points to create acute and subacute models. Motor analysis was performed at 0, 3, 7, 14, and 21 days post-injection. Tyrosine hydroxylase (TH) staining revealed progressive damage of neurons in the substantia nigra compacta (SNc) and reduced striatal fibers in MPTP-treated animals. By using MALDI-MSI, we identified changes in phosphatidylcholine (PC) profiles in the brains of MPTP-treated animals. Polyunsaturated PCs, including PC 36:4 (16:0/20:4), PC 38:6 (16:0/22:6), and PC 40:8 (18:2/22:6), were decreased in the MPTP-treated groups. These reductions were time-dependent and were more pronounced in the subacute MPTP-treated group. The loss of dopamine neurons caused by MPTP may be associated with the selective loss of polyunsaturated PCs in brain membranes, indicating that lipid metabolism and membrane structural alterations may contribute to the pathology of PD. Full article

Background: Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, accompanied by neuromelanin loss. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) enables in vivo visualization of these changes; however, its diagnostic and clinical utility remains incompletely defined. This study evaluated the feasibility, reliability, and biological sensitivity of semi-automated NM-MRI–based substantia nigra volumetry in PD. Methods: In this prospective case–control study, 50 participants (25 PD patients and 25 healthy controls) underwent 3T NM-sensitive MRI using a high-resolution T1-weighted spin-echo sequence. Semi-automated segmentation of hyperintense substantia nigra regions was performed using Mango v3.5.1, with intracranial volume normalization derived from FreeSurfer v7.3. Four participants were excluded due to motion artifacts, yielding a final cohort of 46 subjects. Clinical assessment included the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III and Hoehn and Yahr (H&Y) staging. Group comparisons, receiver operating characteristic (ROC) analysis, and reliability testing using intraclass correlation coefficients (ICC) were performed. Results: Corrected substantia nigra volume was significantly reduced in PD patients compared with controls (18% reduction; p = 0.039, Mann–Whitney U test). Semi-automated measurements demonstrated excellent agreement with manual segmentation (ICC = 0.945). ROC analysis showed moderate discriminative performance for corrected volume (AUC = 0.700; sensitivity 68.4%, specificity 74.1%). No significant correlation was observed between corrected substantia nigra volume and UPDRS-III motor scores, while a trend toward lower SNc volume was observed with advancing H&Y stage. Conclusions: Semi-automated NM-MRI volumetry detects biologically meaningful substantia nigra volume loss in early-stage Parkinson’s disease with high measurement reliability. However, diagnostic performance was moderate and insufficient for standalone clinical diagnosis or motor severity prediction. These findings support the role of NM-MRI as a complementary imaging marker within multimodal diagnostic and research frameworks rather than as an independent diagnostic tool. Full article

The PRDM (PR domain-containing) family consists of transcriptional regulators characterized by a PR (PRDI-BF1 and RIZ homology) domain, a subtype of the SET domain, and a variable number of zinc finger motifs. Nineteen PRDM family members have been identified in both mice and humans, and increasing evidence supports their roles as epigenetic regulators in development and disease. PRDM proteins share a conserved structure, comprising an N-terminal PR domain with potential histone methyltransferase activity and C-terminal C2H2-type zinc fingers involved in protein–protein, protein–RNA, and protein–DNA interactions. Recent studies indicate that multiple PRDM family members are involved in the regulation of the neuro-motor system, including neural lineage specification, neuronal differentiation, motor function maintenance, and neuromuscular-related pathological processes. This review summarizes current evidence on the functions and regulatory mechanisms of PRDM family members in the neuro-motor system. Overall, PRDM family members act as important epigenetic regulators in the neuro-motor system. Clarifying their molecular mechanisms may contribute to a better understanding of neuro-motor regulation and provide a theoretical basis for future research in exercise and movement science. Full article