Search Results (74)

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta along with the aggregation of α-synuclein in Lewy bodies. Among the pathological mechanisms involved is the alteration of iron homeostasis, which promotes oxidative stress and neuronal damage. Despite therapeutic advances, today, no treatment is available to modify the course of the disease. In this study, we investigated for the first time the neuroprotective potential of bovine lactoferrin (bLf) in both its Native (Nat-) and Holo forms, using rotenone-treated N1E-115 cells to mimic PD phenotype. The results showed that the Nat-bLf was more effective than Holo-bLf in counteracting rotenone-induced cytotoxicity and neurite retraction, preserving neuronal morphology and promoting neuritogenesis, as evidenced by increased β3-Tubulin and Growth-Associated Protein-43 markers (GAP-43). Both forms of bLf preserved Tyrosine Hydroxylase (TH) levels, crucial for dopamine synthesis, reduced the DNA damage marker γ-H2Ax and prevented rotenone-induced downregulation of Divalent Metal Transporter-1 (DMT-1) and Ferroportin (Fpn), key proteins involved in iron uptake and release, thereby limiting intracellular iron accumulation. Notably, only Nat-bLf reduced the levels of α-synuclein and markers of oxidative damage. Conversely, Holo-bLf exhibited pro-oxidant effects and increased α-synuclein accumulation even in absence of rotenone. Overall, these results highlight the differential neuroprotective effects of both Nat- and Holo-form, resulting from their distinct iron saturation level and their ability to modulate protein expression, with the native form emerging as a promising candidate for therapeutic strategies to counteract PD-associated neurodegeneration. Full article

Background. MiR-218 is a micro-RNA expressed in two isoforms (miR-218-1 and miR-218-2) in the brain and, within the mesencephalic area, it represents a specific regulator of differentiation and functional maturation of the dopamine-releasing neurons (DAn). Deletion of miR-218 isoforms within the midbrain alters the expression of synaptic mRNAs, the neuronal excitability of DAn of the substantia nigra pars compacta (SNpc), and their ability to release dopamine (DA) within the dorsal striatum. Objectives. Here we have investigated if miR-218 impacts the function of the DAn population adjacent to SNpc, the mesencephalic ventral tegmental area (VTA) innervating the nucleus accumbens (NAcc), and the medial prefrontal cortex. Methods. With the use of miR-218-1, miR-218-2, and double conditional knock-out mice (KO1, c-KO2, c-dKO), we performed electrophysiological recordings in VTA DAn to investigate firing activity, measurements of DA release in NAcc slices by constant potential amperometry (CPA), and in vivo behavioral analysis. Results. We find that KO1 VTA neurons display hyperexcitability in comparison with c-KO2, c-dKO, and wild type (WT) neurons. DA efflux in the NAcc core and shell is reduced in all single- and double-conditional KO striatal slices in comparison with controls. The KO1 mice display a tendency toward an anxiety-like trait, as revealed by the elevated plus maze test. Conclusions. Our data indicate that miR-218-1 is the isoform that mainly regulates VTA DA neuron excitability whereas both miR-218-1 and miR-218-2 impair DA release in the mesoaccumbens pathway. Full article

The pathogenesis and pathophysiology of Huntington’s disease (HD) are still incompletely understood, despite the remarkable advances in identifying the molecular effects of the Htt mutation in this disease. Clinical positron emission tomography studies suggest that phosphodiesterase 10A (PDE10A) declines earlier than dopamine D1 and D2 receptors in HD, indicating that it might serve as a key molecular marker in understanding disease mechanisms. In movement disorders, mutations in the genes encoding PDE10A and G-protein α subunit (Gα_olf), both critical cAMP regulators in striatal spiny projection neurons, have been linked to chorea and dystonia. These observations highlight the potential importance of striatal cyclic AMP (cAMP) signaling in these disorders, but how such dysfunction could come is unknown. Here, we suggest that a key to understanding signaling dysfunction might be to evaluate these messenger systems in light of the circuit-level compartmental organization of the caudoputamen, in which there is particular vulnerability of the striosome compartment in HD. We developed machine learning algorithms to define with high precision and reproducibility the borders of striosomes in the brains of Q175 knock-in (Q175KI) HD mice from 3–12 months of age. We demonstrate that the expression of multiple molecules, including Gα_olf, PDE10A, dopamine D1 and D2 receptors, and adenosine A2A receptors, is significantly reduced in the striosomes of Q175KI mice as compared to wildtype controls, across 3, 6, and 12 months of age. By contrast, mu-opioid receptor (MOR1) expression is uniquely upregulated, suggesting a compartment-specific and age-dependent shift in molecular profiles in the Q175KI HD mouse model caudoputamen. These differential changes may serve as a useful platform to determine factors underlying the greater vulnerability of striatal projection neurons in the striosomes than in the matrix in HD. Full article

Background: Parkinson’s disease (PD) involves progressive dopaminergic neuron degeneration and motor deficits. Oligodendrocyte dysfunction contributes to PD pathogenesis through impaired myelination. Methods: Single-nucleus RNA sequencing (snRNA-seq) of PD mice revealed compromised oligodendrocyte differentiation and STAT5B downregulation. Pseudotemporal trajectory analysis via Monocle2 demonstrated impaired oligodendrocyte maturation in PD oligodendrocytes, correlating with reduced myelin-related gene expression (Sox10, Plp1, Mbp, Mog, Mag, Mobp). DoRothEA-predicted regulon activity identified STAT5B as a key transcriptional regulator. Results: Oligodendrocyte-specific STAT5B activation improved myelin integrity, as validated by Luxol Fast Blue staining and transmission electron microscopy; attenuated dopaminergic neuron loss; and improved motor function. Mechanistically, STAT5B binds the MBP promoter to drive transcription, a finding confirmed by the luciferase assay, while the DNMT3A-mediated hypermethylation of the STAT5B promoter epigenetically silences its expression, as verified by MethylTarget sequencing and methylation-specific PCR. Conclusions: DNMT3A inhibited the expression of STAT5B by affecting its methylation, which reduced the transcription of MBP, caused oligodendrocyte myelin damage, and eventually led to dopamine neuron damage and motor dysfunction in an MPTP-induced mouse model. This DNMT3A-STAT5B-MBP axis underlies PD-associated myelin damage, connecting epigenetic dysregulation with oligodendrocyte dysfunction and subsequent PD pathogenesis. Full article

In the freshwater snail L. stagnalis, two hours of shallow water crawling exercise are accompanied by the formation of memory, metabolic, neuronal, and behavioral changes, such as faster orientation in a novel environment. Interestingly, rest following exercise enhances serotonin and dopamine metabolism linked to the formation of memory and adaptation to novel conditions. However, the underlying transcriptional responses are not characterized. In this paper, we show that, while two hours of forced crawling exercise in L. stagnalis produce significant changes in nervous system gene expression, the subsequent rest induces a completely distinct transcriptional program. Chromatin-modifying, vesicle transport, and cell cycle genes were induced, whereas neurodevelopmental, behavioral, synaptic, and hormone response genes were preferentially repressed immediately after two hours of exercise. These changes were normalized after two hours of the subsequent rest. In turn, rest induced the expression of genes functioning in neuron differentiation and synapse structure/activity, while mitotic, translational, and protein degradation genes were repressed. Our findings are likely relevant to the physiology of exercise, rest, and learning in other species. For example, chronic voluntary exercise training in mice affects the expression of many homologous genes in the hippocampus. Moreover, in humans, homologous genes are pivotal for normal development and complex neurological functions, and their mutations are associated with behavioral, learning, and neurodevelopmental abnormalities. Full article

Schizophrenia is a chronic and severe psychiatric disorder affecting approximately 1% of the global population, characterized by disrupted synaptic plasticity and brain connectivity. While substantial evidence supports its classification as a neurodevelopmental disorder, non-canonical neurodegenerative features have also been reported, with increasing attention given to astrocytic dysfunction. Overall, in this study, we explore the role of astrocytes as a structural and functional link between neurodevelopment and neurodegeneration in schizophrenia. Specifically, we examine how astrocytes contribute to forming an aberrant substrate during early neurodevelopment, potentially predisposing individuals to later neurodegeneration. Astrocytes regulate neurotransmitter homeostasis and synaptic plasticity, influencing early vulnerability and disease progression through their involvement in Ca²⁺ signaling and dopamine–glutamate interaction—key pathways implicated in schizophrenia pathophysiology. Astrocytes differentiate via nuclear factor I-A, Sox9, and Notch pathways, occurring within a neuronal environment that may already be compromised in the early stages due to the genetic factors associated with the ‘two-hits’ model of schizophrenia. As a result, astrocytes may contribute to the development of an altered neural matrix, disrupting neuronal signaling, exacerbating the dopamine–glutamate imbalance, and causing excessive synaptic pruning and demyelination. These processes may underlie both the core symptoms of schizophrenia and the increased susceptibility to cognitive decline—clinically resembling neurodegeneration but driven by a distinct, poorly understood molecular substrate. Finally, astrocytes are emerging as potential pharmacological targets for antipsychotics such as clozapine, which may modulate their function by regulating glutamate clearance, redox balance, and synaptic remodeling. Full article

Background/Objectives: Parkinson’s Disease is a prevalent neurodegenerative disorder affecting millions worldwide, primarily marked by motor and non-motor symptoms due to the degeneration of dopamine-producing neurons. Despite the absence of a cure, current treatments focus on symptom management, often relying on pharmacotherapy and surgical interventions. Early diagnosis remains a critical challenge, particularly in underserved areas, as existing diagnostic protocols lack standardization and accessibility. This paper proposes a novel framework for the diagnosis and severity classification of PD using video data captured in uncontrolled environments. Methods: Leveraging deep learning techniques, our approach synthesizes Skeleton Energy Images (SEIs) from gait sequences and employs three advanced models—a Convolutional Neural Network (CNN), a Residual Network (ResNet), and a Vision Transformer (ViT)—to analyze these images. Our methodology allows for the accurate detection of PD and differentiation of its severity without requiring specialized equipment or professional oversight. The dataset used consists of labeled videos capturing the early stages of the disease, facilitating the potential for timely intervention. Results: The four models performed very accurately during the training phase. In fact, an accuracy higher than 99% was achieved by the ViT and ResNet models. Moreover, a lesser accuracy of 90% was achieved by the CNN five-layer model. During the test phase, only the best-performing models from the training experiments were tested. The ResNet-18 model has achieved a 100% accuracy. However, the ViT and the CNN five-layer models have achieved, respectively, 99.96% and 96.40% test accuracy. Conclusions: The results demonstrate high accuracy, highlighting the framework’s capabilities, and in particular the effectiveness of the workflow used for generating the SEI images. Given the nature of the dataset used, the proposed framework stands to function as a cost-effective and accessible tool for early PD detection in various healthcare settings. This study contributes to the advancement of mobile health technologies, aiming to enhance early diagnosis and monitoring of Parkinson’s Disease. Full article

The TaqIA polymorphism is a marker of both the Ankyrin Repeat and Kinase Domain containing I gene (ANKK1) encoding a RIP-kinase, and the DRD2 gene for the dopamine receptor D2. Despite a large number of studies of TaqIA in addictions and other psychiatric disorders, there is difficulty in interpreting this genetic phenomenon due to the lack of knowledge about ANKK1 function. In SH-SY5Y neuroblastoma models, we show that ANKK1 interacts with the synapse protein FERM ARH/RhoGEF and Pleckstrin Domain 1 (FARP1), which is a guanine nucleotide exchange factor (GEF) of the RhoGTPases RAC1 and RhoA. ANKK1–FARP1 colocalized in F-ACTIN-rich structures for neuronal maturation and migration, and both proteins activate the Wnt/PCP pathway. ANKK1, but not FARP1, promotes neuritogenesis, and both proteins are involved in neuritic spine outgrowth. Notably, the knockdown of ANKK1 or FARP1 affects RhoGTPases expression and neural differentiation. Additionally, ANKK1 binds WGEF, another GEF of Wnt/PCP, regulating its interaction with RhoA. During neuronal differentiation, ANKK1–WGEF interaction is downregulated, while ANKK1–FARP1 interaction is increased, suggesting that ANKK1 recruits Wnt/PCP components for bidirectional control of F-ACTIN assembly. Our results suggest a brain structural basis in TaqIA-associated phenotypes. Full article

Parkinson’s disease (PD) affects movement; however, most patients with PD also develop nonmotor symptoms, such as hyposmia, sleep disorder, and depression. Dopamine levels in the brain have a critical influence on movement control, but other neurotransmitters are also involved in the progression of PD. This study analyzed the fluctuation of neurotransmitters in PC12 cells during neurogenesis and neurodegeneration by performing mass spectrometry. We found that the dopaminergic metabolism pathway of PC12 cells developed vigorously during the neuron differentiation process and that the neurotransmitters were metabolized into 3-methoxytyramine, which was released from the cells. The regulation of the intracellular and extracellular concentrations of adenosine indicated that adenine nucleotides were actively utilized in neural differentiation. Moreover, we exposed the differentiated PC12 cells to rotenone, which is a suitable material for modeling PD. The cells exposed to rotenone in the early stage of differentiation exhibited stimulated serotoninergic metabolism, and the contents of the serotoninergic neurotransmitters returned to their normal levels in the late stage of differentiation. Interestingly, the nondifferentiated cells can resist the toxicant rotenone and produce normal dopaminergic metabolites. However, when differentiated neuron cells were exposed to rotenone, they were seriously damaged, leading to a failure to produce dopaminergic neurotransmitters. In the low-dosage damage process, the amino acids that functioned as dopaminergic pathway precursors could not be absorbed by the cells, and dopamine and L-dopa were secreted and unable to be reuptaken to trigger the cell damage. Full article

This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according to the concept of multifunctional nanomedicine where multiple biological roles are combined into a single nanocarrier and prepared by the melt emulsification method employing the self-emulsifying Gelucire^® 50/13 as lipid matrix. The resulting DA-CIT-SLNs were characterized regarding particle size, surface charge, encapsulation efficiency, morphology, and physical stability. Differential scanning calorimetry, FT-IR, and X ray diffraction studies were carried out to gain information on solid-state features, and in vitro release tests in simulated nasal fluid (SNF) were performed. Monitoring the particle size at two temperatures (4 °C and 37 °C), the size enlargement observed over the time at 37 °C was lower than that observed at 4 °C, even though at higher temperature, color changes occurred, indicative of possible neurotransmitter decomposition. Solid-state studies indicated a reduction in the crystallinity when DA and CIT are co-encapsulated in DA-CIT-SLNs. Interestingly, in vitro release studies in SNF indicated a sustained release of DA. Furthermore, DA-CIT SLNs displayed high cytocompatibility with both human nasal RPMI 2650 and neuronal SH-SY5Y cells. Furthermore, OxyBlot assay demonstrated considerable potential to assess the protective effect of antioxidant agents against oxidative cellular damage. Thus, such protective effect was shown by DA-CIT-SLNs, which constitute a promising formulation for PD application. Full article

Human individual differences in brain cytochrome P450 (CYP) metabolism, including induction, inhibition, and genetic variation, may influence brain sensitivity to neurotoxins and thus participate in the onset of neurodegenerative diseases. The aim of this study was to explore the modulation of CYPs in neuronal cells. The experimental approach was focused on differentiating human neuroblastoma SH-SY5Y cells into a phenotype resembling mature dopamine neurons and investigating the effects of specific CYP isoform induction. The results demonstrated that the differentiation protocols using retinoic acid followed by phorbol esters or brain-derived neurotrophic factor successfully generated SH-SY5Y cells with morphological neuronal characteristics and increased neuronal markers (NeuN, synaptophysin, β-tubulin III, and MAO-B). qRT-PCR and Western blot analysis showed that expression of the CYP 1A1, 3A4, 2D6, and 2E1 isoforms was detectable in undifferentiated cells, with subsequent increases in CYP 2E1, 2D6, and 1A1 following differentiation. Further increases in the 1A1, 2D6, and 2E1 isoforms following β-naphthoflavone treatment and 1A1 and 2D6 isoforms following ethanol treatment were evident. These results demonstrate that CYP isoforms can be modulated in SH-SY5Y cells and suggest their potential as an experimental model to investigate the role of CYPs in neuronal processes involved in the development of neurodegenerative diseases. Full article

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, primarily associated with dopaminergic neuron depletion in the Substantia Nigra. Current treatment focuses on compensating for dopamine (DA) deficiency, but the blood–brain barrier (BBB) poses challenges for effective drug delivery. Using differentiated SH-SY5Y cells, we investigated the co-administration of DA and the antioxidant Grape Seed Extract (GSE) to study the cytobiocompability, the cytoprotection against the neurotoxin Rotenone, and their antioxidant effects. For this purpose, two solid lipid nanoparticle (SLN) formulations, DA-co-GSE-SLNs and GSE-ads-DA-SLNs, were synthesized. Such SLNs showed mean particle sizes in the range of 187–297 nm, zeta potential values in the range of −4.1–−9.7 mV, and DA association efficiencies ranging from 35 to 82%, according to the formulation examined. The results showed that DA/GSE-SLNs did not alter cell viability and had a cytoprotective effect against Rotenone-induced toxicity and oxidative stress. In addition, this study also focused on the evaluation of Alpha-synuclein (aS) levels; SLNs showed the potential to modulate the Rotenone-mediated increase in aS levels. In conclusion, our study investigated the potential of SLNs as a delivery system for addressing PD, also representing a promising approach for enhanced delivery of pharmaceutical and antioxidant molecules across the BBB. Full article

High levels of alcohol intake alter brain gene expression and can produce long-lasting effects. FK506-binding protein 51 (FKBP51) encoded by Fkbp5 is a physical and cellular stress response gene and has been associated with alcohol consumption and withdrawal severity. Fkbp5 has been previously linked to neurite outgrowth and hippocampal morphology, sex differences in stress response, and epigenetic modification. Presently, primary cultured Fkbp5 KO and WT mouse neurons were examined for neurite outgrowth and mitochondrial signal with and without alcohol. We found neurite specification differences between KO and WT; particularly, mesh-like morphology was observed after alcohol treatment and confirmed higher MitoTracker signal in cultured neurons of Fkbp5 KO compared to WT at both naive and alcohol-treated conditions. Brain regions that express FKBP51 protein were identified, and hippocampus was confirmed to possess a high level of expression. RNA-seq profiling was performed using the hippocampus of naïve or alcohol-injected (2 mg EtOH/Kg) male and female Fkbp5 KO and WT mice. Differentially expressed genes (DEGs) were identified between Fkbp5 KO and WT at baseline and following alcohol treatment, with female comparisons possessing a higher number of DEGs than male comparisons. Pathway analysis suggested that genes affecting calcium signaling, lipid metabolism, and axon guidance were differentially expressed at naïve condition between KO and WT. Alcohol treatment significantly affected pathways and enzymes involved in biosynthesis (Keto, serine, and glycine) and signaling (dopamine and insulin receptor), and neuroprotective role. Functions related to cell morphology, cell-to-cell signaling, lipid metabolism, injury response, and post-translational modification were significantly altered due to alcohol. In summary, Fkbp5 plays a critical role in the response to acute alcohol treatment by altering metabolism and signaling-related genes. Full article

Tuberoinfundibular dopamine (TIDA) neurons have cell bodies located in the arcuate nucleus of the mediobasal hypothalamus. They project to the external zone of the median eminence, and the dopamine (DA) released there is carried by the hypophysial portal vasculature to the anterior pituitary. The DA then activates D2 receptors to inhibit prolactin (PRL) secretion from lactotrophs. The TIDA neuronal population is the principal regulatory factor controlling PRL secretion. The neuroendocrine role subserved by TIDA neurons sets them apart from other dopaminergic populations like the nigrostriatal and mesolimbic DA neurons. TIDA neurons exhibit intrinsic oscillatory fluctuations in their membrane potential that give rise to phasic firing and bursting activity. TIDA neuronal activity is sexually differentiated and modulated by gonadal hormones and PRL, as well as an array of small molecule and peptide neurotransmitters. This review covers these characteristics. Full article

Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson’s disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model. Full article