ACS Chemical Neuroscience最新文献

The synaptic vesicle cycle is a critical process that ensures efficient neurotransmission across synaptic junctions, facilitating proper communication within the neuronal circuits. This cycle comprises several tightly regulated steps, including vesicle biogenesis, fusion with the presynaptic membrane, recycling, and degradation, all of which are essential for maintaining synaptic function. Specialized proteins orchestrate the molecular machinery responsible for coordinating vesicle trafficking throughout each stage of the cycle. In recent years, research has highlighted the emerging role of epigenetic regulation in modulating the synaptic vesicle cycle. Epigenetic modifications, such as DNA methylation, histone acetylation, and microRNA expression, regulate vesicle dynamics by modulating key stages of the vesicle trafficking cycle, that in turn affects neurotransmitter release and synaptic plasticity. These regulatory mechanisms ensure synaptic health and proper neuronal communication, while their disruption has been linked to synaptopathies, including autism, schizophrenia, Parkinson’s, and Alzheimer’s diseases. By examining both molecular and epigenetic factors, this review provides valuable insights into how gene expression and protein function are intricately involved in the regulation of the synaptic vesicle cycle. It highlights the importance of key events in regulating the synaptic vesicle cycle, their potential epigenetic drivers, and their relevance to addressing synaptic dysfunctions in various neurological disorders.

Gamma-aminobutyric acid type A receptors (GABA_ARs) are essential for maintaining the excitation–inhibition balance in the central nervous system. Genetic variations of GABA_ARs result in a variety of neurological disorders, such as epilepsy. A key pathogenic mechanism involves protein misfolding and defective assembly of GABA_ARs in the endoplasmic reticulum (ER), resulting in impaired surface expression and loss of function. Here, we investigated three trafficking-deficient variants of the GABA_AR α1 subunit (GABRA1), including D219N (ClinVar Variation ID: 127232), G251D (Variation ID: 419523), and P260L. We demonstrated that selective pharmacological activation of the IRE1/XBP1s signaling arm of the unfolded protein response using IXA62, IXA554, and IXA105 increases total and surface protein levels of all three α1 variants without affecting wild-type receptor protein levels in HEK293T cells. Patch-clamping recordings further showed that treatment with IXA62, IXA554, and IXA105 increases the peak GABA-evoked current amplitudes in HEK293T cells expressing α1(D219N) and α1(G251D). Mechanistic analyses revealed that IXA62 and IXA554 remodel the GABA_AR-associated proteostasis network by promoting folding and anterograde trafficking while inhibiting degradation in HEK293T cells expressing α1(D219N) variant and human iPSC-derived neurons carrying α1(G251D) variant. These results suggest that selective IRE1/XBP1s activation pharmacologically can be further developed to provide a potential therapeutic avenue for genetic epilepsies caused by GABA_AR trafficking defects.

Neurological disorders (NDs) represent a significant global health challenges, with neurodegeneration being a common pathological feature. Recent investigations indicate the involvement of gut microbiota-derived metabolites in these disorders, such as neuroinflammation, oxidative stress, and cognitive decline. The gut–brain axis, a communication network between the gut and the central nervous system (CNS), is influenced by microbial metabolites, which can cross the blood–brain barrier and impact brain function. Key metabolites such as trimethylamine N-oxide (TMAO), para-cresol sulfate (pCS), 4-ethylphenyl sulfate (4-EPS), and indoxyl sulfate (IS) have been linked with the progression of neurological disorders. TMAO disrupts blood–brain barrier integrity, promotes oxidative stress, and activates microglial cells, which lead to the apoptosis of neurons, resulting in neuroinflammation. This could also result in psychiatric changes and behavioral disorders. pCS produced from gut bacteria metabolizing dietary proteins is correlated with amplified oxidative stress, neuroinflammation, and cognitive impairments in disorders like Parkinson’s disease and Alzheimer’s disease. Similarly, elevated 4-EPS levels are linked to autism spectrum disorder, contributing to anxiety-like behavior and blood–brain barrier disruption. Understanding the mechanisms by which gut-derived metabolites affect neurological health could lead to novel therapeutic strategies that can target gut microbiota for the medication and treatment of neurological disorders. Dietary precursors and gut microbiota metabolites, modulated by probiotics, prebiotics, postbiotics, and synbiotics, play a critical role in maintaining microbiota homeostasis and influencing neurological health, needing sophisticated biosensors to enable real-time monitoring and early intervention in disorders linked to gut metabolite imbalances.

Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental condition characterized by difficulties in social interactions and communication, alongside repetitive behaviors and restricted interests. Its etiology is a complex etiology involving genetic, environmental, and epigenetic factors, with significant contributions from mutations in synaptic proteins, including neuroligins (NLGNs), neurexins (NRXNs), and SHANK family proteins. Structural changes caused by mutations in these proteins can lead to synaptic dysfunction, disrupt scaffolding, and impact neuronal circuitry, which reflects the symptoms of ASD. The purpose of this study is to compile the most recent findings regarding protein structure and how specific mutations in these proteins contribute to ASD. This systematic review conducted a comprehensive analysis of research published from 2014 to 2024, collected from the Web of Science and Scopus databases, and the protein structure was collected from the Protein Data Bank. Research that employed cryogenic electron microscopy, nuclear magnetic resonance spectroscopy, and other advanced structural biology methods for molecular modeling was prioritized. After evaluating the findings of the final 40 studies, mutations in the synaptic proteins SHANK3 (G54W, L47P, G250D, R12C, L68P), SHANK2 (S557N), NLGN3 (R451C), NLGN4 (R101Q), and NRXN1 destabilize protein structure, reduce synaptic adhesion, and disrupt neurotransmitter clustering, which influences ASD symptoms. Advanced techniques reveal the molecular structure underlying ASD in animal models, which provides interventions like gene transplantation that can mitigate the effects of these mutations. However, challenges persist in finding treatments for the numerous molecular mechanisms contributing to ASD, emphasizing the need for further research into the structure of all ASD-related proteins.

Neuraxial opioids are routinely administered for pain management, but patients unavoidably suffer from irritating itch. The NMDAR-Akt signaling pathway is strongly implicated in morphine-induced tolerance and pain pathogenesis. Given that pain and itch share some common neurocircuits, this study aimed to evaluate the therapeutic potential of targeting this pathway in morphine-induced pruritus. Acute pruritus was induced in mice through intrathecal morphine injection. We assessed morphine-induced scratching behavior, analgesic effects, and spinal phosphorylation of NR2B and Akt. The roles of NMDAR antagonist, NR2B antagonist, Akt antagonist and agonist were investigated to elucidate the mechanisms underlying morphine-induced itch. Results showed coadministration of NMDAR or NR2B antagonists with morphine dose-dependently reduced morphine-induced scratching behavior. Inhibition of Akt totally abolished pruritus, whereas activation of Akt potentiated scratching responses. These interventions did not significantly affect morphine’s antinociception. Furthermore, morphine-induced spinal Akt phosphorylation was reduced by NMDAR, NR2B, and Akt antagonists while enhanced by Akt agonist, with phosphorylation levels correlated with scratching behavior. The study concludes that intrathecal morphine induces pruritus through spinal upregulation of the NMDAR-Akt pathway in mice, highlighting potential therapeutic targets for relieving morphine-induced pruritus in clinical settings.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder lacking definitive diagnostic tests. To identify new diagnostic biomarkers, we employed glycoproteomics-mass spectrometry (MS) to investigate dynamic changes in protein N-glycosylation across the serum, urine, and saliva of PD patients. Our comparative analysis of differentially expressed glycoproteins (DEGs) between PD patients and healthy controls (HCs) revealed distinct patterns. Specifically, ATPase phospholipid transporter 11B (ATP11B) was significantly upregulated in the serum of PD patients, while urine and saliva showed an opposite trend. Other key findings included elevated myeloperoxidase (MPO) in urine and clusterin (CLU) in serum. Zinc-α-2-glycoprotein (AZGP1), detected in all three biofluids, displayed increased sialylation and core fucosylation in serum but decreased levels in the saliva and urine of PD patients, along with a distinct bifucosylation pattern in saliva. These glycoprotein expression changes were further validated using enzyme-linked immunoassay (ELISA). Pathway analysis indicated that these DEGs are primarily involved in inflammatory response, complement activation, and synaptic plasticity, suggesting that glycosylation dysregulation may contribute to PD progression by modulating neuroinflammation and protein homeostasis. This study represents the first comprehensive analysis of multibiofluid N-glycosylation in PD. The findings offer potential biomarkers and provide insights into the molecular mechanisms of the disease, which could ultimately inform early diagnosis and the development of targeted therapies.

This study investigated the neuroprotective effects of vitamin D (VD) supplementation in mitigating chemotherapy-induced cognitive dysfunction (CICD) induced by doxorubicin (DOX) in a mouse model. Given the widespread impact of chemotherapy-induced neurotoxicity, the purpose was to explore the potential of VD to alleviate cognitive impairment and its underlying molecular mechanisms. We administered cholecalciferol emulsion (CCE), a VD analog, and assessed its effects on behavior, oxidative stress, inflammation, and neuronal integrity. Our findings demonstrate that CCE treatment significantly improved cognitive function, reduced oxidative stress, and attenuated neuroinflammation in the hippocampus. Furthermore, molecular analysis revealed that VD supplementation modulated the Wnt/β-catenin signaling pathway, notably through the suppression of SFRP1 and activation of PPAR-γ. These results suggest that VD exerts its neuroprotective effects by regulating key signaling pathways involved in neuroprotection, making it a promising candidate for therapeutic strategies to mitigate doxorubicin-induced cognitive decline.

Neuromelanin is a dark pigment present in the human brain and involved in the onset of Parkinson’s disease. Since natural pigment can only be extracted from the human brain in very small quantities, synthetic models of neuromelanin have been developed in recent years for research purposes, consisting of melanin conjugates and proteins made up of dopamine and β-lactoglobulin. Here, we studied the influence of nitrative stress on the synthesis of neuromelanin models, as it is known that reactive nitrogen species are present in vivo under pathophysiological conditions. HPLC-MS/MS analysis and ¹H NMR and UV–vis absorption spectra show that nitration on the protein component does not affect the conjugate synthesis, while increasing nitration on the melanic component, by replacing dopamine with its nitrate derivative, 6-nitrodopamine, gradually inhibits the melanization. Moreover, although 6-nitrodopamine is not able to trigger melanization alone, in the presence of dopamine, it is incorporated into the conjugate. This study represents a step forward toward the synthesis of models that are increasingly similar to human neuromelanin, considering the influence of nitrative stress on neuromelanin pigment properties and biosynthesis.

Depression, characterized by a persistent low mood and apathy, is classified as a mental illness. Lipopolysaccharide (LPS), an inflammatory inducer, reduces plasma concentrations of hydrogen sulfide (H₂S) and gamma-aminobutyric acid (GABA) in mice, resulting in depressive-like behaviors. H₂S, an endogenous gaseous signaling molecule, is crucial for maintaining normal physiological functions of the central nervous system. GABA, an inhibitory neurotransmitter, has been demonstrated to mitigate depression-like behaviors in mice subjected to chronic stress. Sodium hydrosulfide (NaHS), an H₂S donor, alleviates LPS-induced depressive-like behaviors in mice; however, its rapid release of H₂S may lead to accumulation and potential toxicity. This study aimed to mimic the body’s natural slow production of H₂S and GABA. To this end, three novel multifunctional donors─BGS, BGF, and BGA─were designed and synthesized. Among them, BGS showed reduced toxicity to HT-22 cells and a sustained release profile in vitro. Furthermore, BGS increased plasma levels of H₂S and GABA in mice, ameliorated LPS-induced depressive-like behaviors, enhanced neuronal count in the hippocampal CA1 subregion, decreased p-NF-κB levels, and upregulated the expression of synaptic proteins SYN and PSD-95. These results suggest that BGS not only elevates plasma H₂S and GABA levels but also inhibits NF-κB activation, enhances synaptic protein expression, and improves synaptic plasticity, thus exerting a multifaceted antidepressant effect.

Ghrelin is an orexigenic hormone secreted mainly in the stomach and small intestine. It has many functions, including appetite stimulation, growth hormone release triggering, and maintaining glucose and energy homeostasis. It has also been linked to many neuroregenerative and neuroprotective activities via its activity on the growth hormone secretagogue receptor 1a (GHS-R1a). In brain tissues, it has been revealed that only the acylated ghrelin (AG) but not the unacylated ghrelin (UAG) has the affinity to GHS-R1a. In addition, AG has been shown to undergo fast enzymatic conversion into the inactive UAG form in the serum. Many experimental trials were conducted to study ghrelin’s effect on Alzheimer’s disease (AD) and Parkinson’s disease (PD), but there have not been systematic reviews made to date. This systematic review highlighted the findings from preclinical trials between 2010 and July 2023, in which ghrelin and/or one of its agonists have been investigated for their effects in treating AD and PD. The search databases used were Embase, Cochrane, and Medline. All articles reviewed were animal studies as there were no clinical trials. The findings on AD showed that AG has demonstrated improved outcomes histopathologically and symptomatically. Meanwhile for PD, AG was found to have neuroprotective effects, especially in the early stage of the disease. This systematic review paves the way for more studies to be done to ensure the applicability of ghrelin and/or its agonists in treating and/or slowing the progression of AD, and early prevention and diagnosis of PD.