Search Results (109)

REM sleep behavior disorder (RBD) represents a prodromal manifestation of Parkinson’s disease (PD), reflecting the breakdown of inhibitory networks extending from the brainstem to the cortex. This review synthesizes pathological, physiological, and behavioral evidence to illustrate how early α-synuclein pathology disrupts REM-sleep atonia and motor automaticity through degeneration of pontomedullary and cholinergic–inhibitory circuits. The resulting failure of inhibitory precision links nocturnal REM sleep without atonia to daytime gait and postural abnormalities, framing RBD as a dynamic systems disorder rather than a purely sleep-related phenomenon. By examining this continuum across neurophysiological, behavioral, and clinical domains, the review highlights current knowledge gaps, particularly regarding the temporal dynamics of degeneration and compensation. It further integrates multimodal biomarkers that capture these transitions in vivo and discusses therapeutic strategies aimed at preserving inhibitory network integrity and delaying phenoconversion to overt Parkinsonian syndromes. Full article

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G₄C₂ repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G₄C₂ repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD. Full article

Neuregulins (NRGs) are ligands of tyrosine kinase receptors from the ErbB family and play multiple developmental roles. NRG1–ErbB signaling regulates myelination and has been associated with amyotrophic lateral sclerosis (ALS) pathology. Given the potential therapeutic relevance of this pathway for motor neuron (MN) diseases, we employed a transgenic (TG) mouse with persistent neuronal overexpression of neuregulin type III (NRG1-III) to investigate its impact on the neuromuscular system. We performed an analysis of phenotypic changes in this TG model, including motor behavior, neuropathological evaluation by immunocytochemistry and ultrastructural examination of the spinal cord, peripheral nerves, and neuromuscular junctions (NMJs). Calcium dynamics in cultured MNs were also examined. We found that cholinergic C-boutons on TG MNs, where NRG1-III typically accumulates, exhibited upregulation of C-bouton-associated proteins and expansion of the subsynaptic cistern (SSC)-associated endoplasmic reticulum. Calcium imaging revealed altered homeostasis in TG MNs, accompanied by the upregulation of molecules linked to axonal plasticity. At NMJs, regressive changes involving autophagic dysregulation were observed. These alterations were accompanied by increased motor activity in behavioral tests. Overall, our findings indicate that persistently elevated NRG1-III signaling compromises MN connectivity and long-term health, a factor to consider when developing therapeutic strategies for neurodegenerative diseases such as ALS. Full article

Background: Degenerin proteins, such as Acid-Sensing Ion Channel 2 (ASIC2) and β Epithelial Na⁺ Channel (βENaC), have been implicated in cardiovascular function. We previously demonstrated that mice lacking normal levels of βENaC and ASIC2 are protected from diet-induced obesity, metabolic disruption, and hepatic steatosis. Methods: To investigate the specific role of βENaC proteins in the progression of metabolic disease, we examined the impact of a high-fat diet (HFD) in the βENaC hypomorph mouse model (βMUT). Body composition and metabolic and behavioral phenotypes were examined in male and female and βMUT and WT mice (n = 6–14/group) fed a normal chow diet (NFD) from weaning until 16 weeks of age, then a 60% kcal-fat diet for 5 weeks. Results: Compared to WT mice, βMUT male mice have reduced lean and total body mass. No remarkable differences in energy expenditure, motor activity, or food consumption patterns were detected. HFD-fed male βMUT mice exhibited reduced liver fat content (mass and Oil Red O staining) yet increased abdominal fat depots. HFD-fed female βMUT mice exhibited lower heart mass. Conclusions: These novel findings suggest a role for βENaC in the maintenance of metabolic homeostasis and adipose tissue distribution. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications. Full article

KMT2C (histone lysine N-methyltransferase 2C, also known as MML3, myeloid/lymphoid or mixed-lineage leukemia 3) is a causal gene for Kleefstra syndrome 2, a rare neurodevelopmental disorder. Recent human genetic studies have identified it as a high-risk gene for autism spectrum disorder (ASD), with 79% of patients harboring KMT2C variants having ASD. However, the causal link between KMT2C haploinsufficiency and ASD remains unclear. KMT2C/MLL3 encodes a histone methyltransferase, a core protein of the KMT2C/D COMPASS (complex proteins associated with Set1) complex, which plays fundamental roles in chromatin modification, occupancy, and gene expression. The expression of KMT2C/Kmt2c peaks during the developmental period in the human/mouse brain, which indicates the critical roles of KMT2C/Kmt2c in neurodevelopment. Here, we investigated the impact of germline Kmt2c haploinsufficiency on autism-like behavioral deficits in mice, which modeled humans carrying diverse KMT2C variants. Compared with Kmt2c^+/+ controls, Kmt2c haploinsufficiency mice had normal motor function without anxiety-like behaviors. Notably, Kmt2c haploinsufficiency mice exhibited autism-like social deficits and increased self-grooming in both males and females, which recapitulated the core phenotypes of ASD patients. Novel object recognition and spatial memory deficits were observed in male and female Kmt2c haploinsufficiency mice. This study reveals a causal link between Kmt2c haploinsufficiency and ASD-like behavioral deficits. These germline Kmt2c haploinsufficiency mice can be used for further studying the molecular mechanisms and developing therapeutic interventions for KMT2C haploinsufficiency-associated behavioral deficits. Full article

Adaptor Protein-1 (AP-1) is a heterotetrameric essential for intracellular vesicular trafficking and polarized localization of somato-dendritic proteins in neurons. Variants in the AP1G1 gene, encoding the gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), have recently been associated with Usmani–Riazuddin syndrome (USRISD, MIM#619467), a very rare human genetic disorder characterized by intellectual disability (ID), speech and neurodevelopmental delays. Here we report a novel variant (c.196G>A; p.Gly66Arg) identified by exome sequencing analysis in a young girl showing overlapping clinical features with USRIS, such as motor and speech delay, intellectual disability and abnormal aggressive behavior. In silico analysis of the missense de novo variant suggested an alteration in AP1G1 protein folding. Patient’s fibroblasts have been studied with immunofluorescence techniques to analyze the intracellular distribution of AP-1. Zebrafish are widely regarded as an excellent vertebrate model for studying human disease pathogenesis, given their transparent embryonic development, ease of breeding, high genetic similarity to humans, and straightforward genetic manipulation. Leveraging these advantages, we investigated the phenotype, locomotor behavior, and CNS development in zebrafish embryos following the microinjection of human wild-type and mutated AP1G1 mRNAs at the one-cell stage. Knockout (KO) of the AP1G1 gene in zebrafish led to death at the gastrula stage. Lethality in the KO AP1G1 fish model was significantly rescued by injection of the human wild-type AP1G1 mRNA, but not by transcripts encoded by the Gly66Arg missense allele. The phenotype was also not rescued when ap1g1−/− zebrafish embryos were co-injected with both human wild-type and mutated mRNAs, supporting the dominant-negative effect of the new variant. In this study, we defined the effects of a new AP1G1 variant in cellular and animal models of Usmani–Riazzudin syndrome for future therapeutic approaches. Full article

Tourette Disorder (TD) is a prevalent neurodevelopmental condition characterized by chronic motor and vocal tics. A mechanistic understanding of both the genetic etiology and brain pathophysiology remains poor. To gain insight into the molecular underpinnings of TD, we have generated a novel mouse model expressing an orthologous human mutation in CELSR3, a high-confidence TD risk gene. This putative damaging de novo variant, R774H, causes an amino acid substitution within the fifth cadherin repeat. Unlike previous Celsr3 TD models and Celsr3 constitutive null mice, mice homozygous for the R774H amino acid substitution are viable. They have grossly normal forebrain development and no changes to the density of cortical and striatal interneuron subpopulations. However, 3D geometric analysis of cortical pyramidal neurons revealed changes to dendritic patterning and the types and distributions of spines. Furthermore, patch clamp recordings in cholinergic interneurons located within the sensorimotor striatum uncovered mild intrinsic hyperexcitability and changes to spine density. Despite these changes, Celsr3^R774H homozygous mice do not show repetitive motor behaviors at baseline nor motor learning impairments. However, Celsr3^R774H homozygous males have sensorimotor gating deficits, a behavioral phenotype observed in both humans with TD and previously reported mouse models. Our findings suggest human mutations in CELSR3 may affect dendritic patterning, spine formation and/or turnover, and the firing properties of neurons within cortico-striatal circuits. Full article

Chronic pain (CP) represents a multidimensional condition in which cognitive and emotional factors shape the individual experience from perception to action. The purpose of this study was to characterize the functional significance of alterations in neural oscillatory dynamics underlying the transition from resting-state to cognitive load across distinct CP phenotypes. Continuous electroencephalographic data were acquired from patients with headache, migraine, and spine-related pain, as well as healthy controls, during rest and three visual–cognitive–motor (VCM) tasks: reaction time, working memory, and associative learning. First, within CP subgroups, we examined cognitive-load-related changes in oscillatory activity. In migraine patients, alpha/beta power attenuation induced during cognitive processing correlated with higher reported pain intensity. Relative to the spine-related pain group, migraine patients exhibited increased occipital alpha and gamma band activity during working memory and associative learning conditions, as a possible neurophysiological signature of cortical hyperexcitability. By comparing a subset of headache patients to healthy controls, we found elevated resting-state delta and gamma activity in the patient group. Under cognitive load conditions, headache patients showed higher power across delta, theta, beta, and gamma frequency bands. Delta and theta activity elicited during the working memory task correlated negatively with pain intensity. Our results demonstrate that the experience of chronic pain is accompanied by frequency-specific alterations in both resting and cognitive-associated oscillatory dynamics, reflecting impaired visual working-memory processing and top–down modulation of behaviorally relevant stimuli. Full article

Autism spectrum disorder (ASD) encompasses a range of conditions, primarily marked by deficits in social behaviors, along with several comorbidities such as sleep abnormalities and motor dysfunction. Recent studies have identified genetic risk factors associated with ASD, including the CAMK4 (calcium/calmodulin-dependent protein kinase 4). However, the molecular mechanisms linking CAMK4 dysregulation and ASD-associated phenotypes remain poorly understood. Here, we used Drosophila melanogaster as a model system to investigate ASD-associated phenotypes in flies with dysregulated CaMKI, the fly homolog of mammalian CAMK4. We show that CaMKI manipulations affect sleep, circadian rhythmicity, and social behavior. Consistent with the higher prevalence of dementia observed in autistic patients, we also observed a significantly enhanced behavioral decline in motor performance and dendritic degeneration in flies expressing RNAi-based CaMKI knockdown in flight motoneurons, suggesting a link between developmental and degenerative processes. As aberrant synaptic pruning is hypothesized to underlie the synaptic phenotypes observed in brains of autistic patients, we examined synaptic phenotypes following CaMKI manipulations using the larval neuromuscular junction (NMJ) and observed miswiring phenotypes suggesting aberrant synaptic refinement. We performed shotgun mass-spectrometry proteomics and identified various molecular candidates, particularly molecules involved in cytoskeleton regulation and chemorepulsion, likely to regulate the phenotypes described here. Thus, our results suggest that CaMKI plays a role in developmental processes and influences aging-dependent degenerative processes, possibly providing mechanistic insight into the genetic basis of ASD etiology and the development of effective treatments. Full article

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social communication deficits, repetitive behaviors, and frequent gastrointestinal comorbidities. Emerging research suggests gut microbiota alterations contribute to ASD symptoms and gastrointestinal dysfunction, but detailed microbial profiles and clinical correlations remain underexplored. Methods: This study analyzed gut microbiota in 45 children aged 2–18 years diagnosed with ASD. Stool samples underwent 16S rRNA gene sequencing. Clinical assessments included ASD diagnostic subtype, adaptive functioning using the Vineland Adaptive Behavior Scale, gastrointestinal symptoms as per the Rome IV criteria, dietary patterns, and demographic variables. Statistical analyses correlated microbiota profiles with clinical features. Results: Gut microbiota composition was significantly influenced by delivery mode, age, sex, and diet. Vaginally delivered children had higher beneficial SCFA-producing bacteria, whereas Cesarean section was linked to increased pathogenic Clostridiales. High-calorie and protein-rich diets correlated with shifts toward pro-inflammatory taxa. Microbial diversity and specific genera correlated with adaptive behavior domains (communication, socialization, motor skills) and severity of gastrointestinal symptoms. Both pro-inflammatory and anti-inflammatory bacteria variably impacted neurodevelopmental outcomes. Conclusions: Gut microbiota composition in children with ASD is shaped by multifactorial influences and connected to neurobehavioral and gastrointestinal phenotypes. The findings of this study support the potential of microbiota-targeted interventions to ameliorate ASD-associated symptoms and improve quality of life. Full article

Background: Absence epilepsy is a common pediatric neurological disorder characterized by brief seizures and lapses in awareness. The relationship between anxiety and absence epilepsy is multifaceted. This study aims to investigate neurobehavioral signs directly and indirectly related to anxiety and potential sex differences in aged WAG/Rij rats, a well-established animal model of absence epilepsy. Methods: A battery of behavioral tests was conducted to assess various aspects of neurobehavior, including anxiety (elevated plus maze), anhedonia (sucrose preference), social function, and associative learning (fear conditioning). Multidimensional metrics assessed cognition, motor function, and exploration strategies, prioritizing anxiety as a key influencing factor. Results: Electroencephalogram (EEG) phenotyping was used to identify epileptic and non-epileptic rats. Traditional anxiety measures in the elevated plus maze did not reveal significant differences between groups. However, the Anxiety Composite Index revealed higher autonomic reactivity in non-epileptic females. Cognitive assessments showed no epilepsy- or sex-related differences in overall learning performance. Females exhibited superior avoidance learning compared males. Among epileptic males, those with poor learning performance also displayed higher anxiety-avoidance scores. Rats with high anxiety levels showed enhanced socio-affective reactivity and passive coping, with no effect on exploratory learning. Conclusions: Our findings highlight the importance of sex-specific analyses and physiological measures in epilepsy research. Neurobehavioral comorbidities in WAG/Rij rat model are significantly influenced by anxiety-like behavioral phenotype. Enhanced phenotyping of rat models of absence epilepsy can improve its translational value in understanding epilepsy-associated psychiatric disorders. Full article

While most of the Alzheimer’s disease (AD) cases are sporadic and manifest after age 65 (late-onset AD, LOAD), a subset of patients develop symptoms earlier in life (early-onset, EOAD) due to mutations in the PSEN1, PSEN2, or APP genes with an autosomal-dominant inheritance pattern (AD-EOAD). In this study, we examined the association between age of onset (AoO) and first clinical manifestation (FCM) with the APOE and DAOA genotypes, previously described as modifiers of clinical phenotypes in LOAD and EOAD in 88 individuals clinically diagnosed with AD-EOAD due to the PSEN1 A431E variant (39 females, 49 males). We classified the population according to their genotype (APOEε2, APOEε3, and APOEε4 and DAOA G/G, G/A, and A/A) and FCM (cognitive, behavioral, motor, and memory impaired). Memory impairment was the most frequent symptom (51%), followed by motor disturbances (31.8%), cognitive symptoms other than memory (10.4%), and behavioral changes (6.8%). We found a significant association between APOE genotype and AoO (p < 0.001), with the APOEε4 allele being linked to a delayed onset (β = 4.04, SE = 1.11, p = 0.0003). Similarly, individuals with the DAOA rs2391191 A/A genotype showed a significantly later AoO compared to G/G carriers (β = 2.13, SE = 0.96, p = 0.0301). No significant association was found between APOE or DAOA genotypes and FCM. The findings suggest that both the APOEε4 allele and DAOA rs2391191 A/A genotype may act as genetic modifiers of AoO, delaying symptom onset in individuals with AD-EOAD. Further research is needed to elucidate the molecular pathways through which APOE and DAOA influence AD-EOAD progression. Full article

Objectives: This study aimed to establish a transgenic mouse model expressing nucleus-localized human α-synuclein (α-syn) to investigate its impact on the central nervous system and behavior and the underlying mechanisms involved. Methods: A nuclear localization sequence (NLS) was added to the end of the human SNCA (hSNCA) gene. Subsequently, an empty vector and a mammalian lentiviral vector of the hSNCA-NLS were constructed. Transgenic mice were generated via microinjection, with genotyping and protein expression confirmed by PCR and western blotting. Only male mice were used in subsequent behavioral and molecular experiments. Immunofluorescence identified the colocalization of human α-syn with the cell nucleus in mouse brain tissues. Behavioral changes in transgenic mice were assessed using open field, rotarod, and O-maze tests. qPCR and Western blotting detected expression levels of genes and proteins related to inflammation, endoplasmic reticulum stress (ERS), and apoptosis. Bulk RNA sequencing was used to screen for differentially expressed genes and signaling pathways. Results: We successfully constructed a transgenic mouse model expressing human α-syn. Human α-syn was widely expressed in the heart, liver, spleen, kidneys, and brain of the mice, with distinct nuclear localization observed. Behavioral assessments demonstrated that, by 2 months of age, the mice exhibited motor dysfunction alongside astrocyte proliferation and neuroinflammation. At 6 months, the elevated expression of ERS-related genes (ATF6, PERK, and IRE1) and activation of the PERK-Beclin1-LC3II pathway indicated progressive ERS. By 9 months, apoptotic events had occurred, accompanied by significant anxiety-like behaviors. Bulk RNA sequencing further identified key differentially expressed genes, including IL-1α, TNF, PERK, BECLIN, GABA, IL-6α, P53, LC3II, NOS, and SPAG, suggesting their involvement in the observed pathological and behavioral phenotypes. Conclusions: The nuclear localization human α-syn transgenic mice were successfully established. These findings demonstrate that nucleus-localized α-syn induces early motor deficits, which are likely mediated by neuroinflammation, whereas later anxiety-like behaviors may result from ERS-induced apoptosis. This model provides a valuable tool for elucidating the role of nuclear α-syn in Parkinson’s disease and supports further mechanistic and therapeutic research. Full article

Background and Objectives: Toe walking (TW) is frequently observed in children with Autism Spectrum Disorder (ASD), yet its clinical significance and association with comorbid conditions remain poorly understood. This study aimed to examine the prevalence of TW in a large Italian cohort of children with ASD and to explore its association with ASD severity, sleep disturbances, feeding behaviors, and gastrointestinal symptoms. Materials and Methods: A total of 289 children with ASD and 289 typically developing controls (TDC), matched for age and sex, were evaluated in a multicentric observational study. TW was assessed during neurodevelopmental evaluations. Sleep quality was assessed using the Sleep Disturbance Scale for Children (SDSC), feeding behaviors via the Brief Autism Mealtime Behavior Inventory (BAMBI), and gastrointestinal symptoms through clinical reporting. Statistical analyses included Chi-square tests, Mann–Whitney U tests, Spearman correlations, and logistic regressions. Results: TW was significantly more prevalent in the ASD group (27.3%) than in TDC (5.5%, p < 0.0001). Within the ASD group, TW occurred in 50.5% of children with Level 3 severity but was absent in Levels 1 and 2 (p < 0.0001). Males exhibited TW more frequently than females. Children with TW had higher SDSC scores (ρ = 0.33, p < 0.0001), though no subscale independently predicted TW. Constipation was reported in 100% of children with Level 3 ASD and was strongly correlated with SDSC total scores (ρ = 0.58, p < 0.0001). The Disorders of Arousal (DA) subscale emerged as an independent predictor of constipation (β = 0.184, p = 0.019). Conclusions: TW in ASD appears to be a marker of greater neurodevelopmental severity and is associated with sleep disturbances and gastrointestinal dysfunction. These findings support the hypothesis that TW may reflect broader dysfunctions involving the gut–brain axis, sensory processing, and motor control. The routine clinical assessment of TW should include the evaluation of sleep and somatic symptoms to better understand the multisystemic nature of ASD phenotypes. Full article