Pub Date : 2024-09-11DOI: 10.3389/fnmol.2024.1470171
Shenjie Wu, Randy W. Schekman
An emerging theme in Parkinson’s disease (PD) is the propagation of α-synuclein pathology as the disease progresses. Research involving the injection of preformed α-synuclein fibrils (PFFs) in animal models has recapitulated the pathological spread observed in PD patients. At the cellular and molecular levels, this intercellular spread requires the translocation of α-synuclein across various membrane barriers. Recent studies have identified subcellular organelles and protein machineries that facilitate these processes. In this review, we discuss the proposed pathways for α-synuclein intercellular transmission, including unconventional secretion, receptor-mediated uptake, endosome escape and nanotube-mediated transfer. In addition, we advocate for a rigorous examination of the evidence for the localization of α-synuclein in extracellular vesicles.
{"title":"Intercellular transmission of alpha-synuclein","authors":"Shenjie Wu, Randy W. Schekman","doi":"10.3389/fnmol.2024.1470171","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1470171","url":null,"abstract":"An emerging theme in Parkinson’s disease (PD) is the propagation of α-synuclein pathology as the disease progresses. Research involving the injection of preformed α-synuclein fibrils (PFFs) in animal models has recapitulated the pathological spread observed in PD patients. At the cellular and molecular levels, this intercellular spread requires the translocation of α-synuclein across various membrane barriers. Recent studies have identified subcellular organelles and protein machineries that facilitate these processes. In this review, we discuss the proposed pathways for α-synuclein intercellular transmission, including unconventional secretion, receptor-mediated uptake, endosome escape and nanotube-mediated transfer. In addition, we advocate for a rigorous examination of the evidence for the localization of α-synuclein in extracellular vesicles.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"13 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.3389/fnmol.2024.1441575
Joanna Rog, Łukasz Łobejko, Michalina Hordejuk, Wojciech Marciniak, Róża Derkacz, Adam Kiljańczyk, Milena Matuszczak, Jan Lubiński, Miłosz Nesterowicz, Małgorzata Żendzian-Piotrowska, Anna Zalewska, Mateusz Maciejczyk, Hanna Karakula-Juchnowicz
Disturbances in pro/antioxidant balance emerge as a crucial element in bipolar disorder (BD). Some studies suggest that treatment effects on trace element concentration in BD. This study aimed to identify (a) the changes related to oxidative stress in BD and their relationship with trace elements engaged in pro/antioxidant homeostasis; (b) BD biomarkers using machine learning algorithm classification and regression tree (C&RT) analysis. 62 individuals with BD and 40 healthy individuals (HC) were included in the study. The concentration of pro/antioxidant state and concentration of selenium, zinc, arsenic in blood were assessed. We found a higher concentration of total antioxidant capacity, catalase, advanced oxidation protein products and a lower concentration of 4-hydroxynonenal (4-HNE), glutathione, glutathione peroxidase (GPx) in BD compared to HC. All examined trace elements were lower in the BD group compared to HC. A combination of two variables, 4-HNE (cut-off: ≤ 0.004 uM/mg protein) and GPx (cut-off: ≤ 0.485 U/mg protein), was the most promising markers for separating the BD from the HC. The area under the receiver operating characteristic curve values for C&RT was 90.5%. Disturbances in the pro/antioxidant state and concentration of trace elements of patients with BD may be a target for new therapeutic or diagnostic opportunity of BD biomarkers.
{"title":"Pro/antioxidant status and selenium, zinc and arsenic concentration in patients with bipolar disorder treated with lithium and valproic acid","authors":"Joanna Rog, Łukasz Łobejko, Michalina Hordejuk, Wojciech Marciniak, Róża Derkacz, Adam Kiljańczyk, Milena Matuszczak, Jan Lubiński, Miłosz Nesterowicz, Małgorzata Żendzian-Piotrowska, Anna Zalewska, Mateusz Maciejczyk, Hanna Karakula-Juchnowicz","doi":"10.3389/fnmol.2024.1441575","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1441575","url":null,"abstract":"Disturbances in pro/antioxidant balance emerge as a crucial element in bipolar disorder (BD). Some studies suggest that treatment effects on trace element concentration in BD. This study aimed to identify (a) the changes related to oxidative stress in BD and their relationship with trace elements engaged in pro/antioxidant homeostasis; (b) BD biomarkers using machine learning algorithm classification and regression tree (C&RT) analysis. 62 individuals with BD and 40 healthy individuals (HC) were included in the study. The concentration of pro/antioxidant state and concentration of selenium, zinc, arsenic in blood were assessed. We found a higher concentration of total antioxidant capacity, catalase, advanced oxidation protein products and a lower concentration of 4-hydroxynonenal (4-HNE), glutathione, glutathione peroxidase (GPx) in BD compared to HC. All examined trace elements were lower in the BD group compared to HC. A combination of two variables, 4-HNE (cut-off: ≤ 0.004 uM/mg protein) and GPx (cut-off: ≤ 0.485 U/mg protein), was the most promising markers for separating the BD from the HC. The area under the receiver operating characteristic curve values for C&RT was 90.5%. Disturbances in the pro/antioxidant state and concentration of trace elements of patients with BD may be a target for new therapeutic or diagnostic opportunity of BD biomarkers.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10eCollection Date: 2024-01-01DOI: 10.3389/fnmol.2024.1487871
Claudia Espinosa-Garcia, Erfan Bahramnejad, Yi Li
{"title":"Editorial: Immune system mechanisms impacting the onset of epilepsy and spontaneous seizures.","authors":"Claudia Espinosa-Garcia, Erfan Bahramnejad, Yi Li","doi":"10.3389/fnmol.2024.1487871","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1487871","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1487871"},"PeriodicalIF":3.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.3389/fnmol.2024.1391092
Iuliana Magdalena Starcea, Ancuta Lupu, Ana Maria Nistor, Maria Adriana Mocanu, Roxana Alexandra Bogos, Alice Azoicai, Diana Cira, Madalina Beldie, Vasile Valeriu Lupu, Ionela Daniela Morariu, Valentin Munteanu, Razvan Tudor Tepordei, Ileana Ioniuc
Pain is a subjective concept which is ever-present in the medical field. Health professionals are confronted with a variety of pain types and sources, as well as the challenge of managing a patient with acute or chronic suffering. An even bigger challenge is presented in the pediatric population, which often cannot quantify pain in a numerical scale like adults. Infants and small children especially show their discomfort through behavioral and physiological indicators, leaving the health provider with the task of rating the pain. Depending on the pathophysiology of it, pain can be classified as neuropathic or nociceptive, with the first being defined by an irregular signal processing in the nervous system and the second appearing in cases of direct tissue damage or prolonged contact with a certain stimulant. The approach is generally either pharmacological or non-pharmacological and it can vary from using NSAIDs, local anesthetics, opiates to physical and psychological routes. Unfortunately, some pathologies involve either intense or chronic pain that cannot be managed with traditional methods. Recent studies have involved nanoparticles with special characteristics such as small dimension and large surface area that can facilitate carrying treatments to tissues and even offer intrinsic analgesic properties. Pediatrics has benefited significantly from the application of nanotechnology, which has enabled the development of novel strategies for drug delivery, disease diagnosis, and tissue engineering. This narrative review aims to evaluate the role of nanotechnology in current pain therapy, with emphasis on pain in children.
{"title":"A cutting-edge new framework for the pain management in children: nanotechnology","authors":"Iuliana Magdalena Starcea, Ancuta Lupu, Ana Maria Nistor, Maria Adriana Mocanu, Roxana Alexandra Bogos, Alice Azoicai, Diana Cira, Madalina Beldie, Vasile Valeriu Lupu, Ionela Daniela Morariu, Valentin Munteanu, Razvan Tudor Tepordei, Ileana Ioniuc","doi":"10.3389/fnmol.2024.1391092","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1391092","url":null,"abstract":"Pain is a subjective concept which is ever-present in the medical field. Health professionals are confronted with a variety of pain types and sources, as well as the challenge of managing a patient with acute or chronic suffering. An even bigger challenge is presented in the pediatric population, which often cannot quantify pain in a numerical scale like adults. Infants and small children especially show their discomfort through behavioral and physiological indicators, leaving the health provider with the task of rating the pain. Depending on the pathophysiology of it, pain can be classified as neuropathic or nociceptive, with the first being defined by an irregular signal processing in the nervous system and the second appearing in cases of direct tissue damage or prolonged contact with a certain stimulant. The approach is generally either pharmacological or non-pharmacological and it can vary from using NSAIDs, local anesthetics, opiates to physical and psychological routes. Unfortunately, some pathologies involve either intense or chronic pain that cannot be managed with traditional methods. Recent studies have involved nanoparticles with special characteristics such as small dimension and large surface area that can facilitate carrying treatments to tissues and even offer intrinsic analgesic properties. Pediatrics has benefited significantly from the application of nanotechnology, which has enabled the development of novel strategies for drug delivery, disease diagnosis, and tissue engineering. This narrative review aims to evaluate the role of nanotechnology in current pain therapy, with emphasis on pain in children.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"159 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.3389/fnmol.2024.1400118
Ning Gao, Meng Li, Weiming Wang, Zhen Liu, Yufeng Guo
The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a “pain switch” through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1’s interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP.
{"title":"The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization","authors":"Ning Gao, Meng Li, Weiming Wang, Zhen Liu, Yufeng Guo","doi":"10.3389/fnmol.2024.1400118","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1400118","url":null,"abstract":"The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a “pain switch” through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1’s interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"99 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.3389/fnmol.2024.1451226
En Zhou, Xuping Xiao, Bin Liu, Zhiqiang Tan, JiaYu Zhong
ObjectiveStudies on feeling of ear fullness (FEF) related to sudden sensorineural hearing loss(SSNHL) are limited. The mechanisms of FEF are unclear. This study aimed to explore the characteristics and related brain activation of SSNHL with FEF.MethodsA total of 269 SSNHL patients were prospectively observed and divided into two groups, with FEF and without FEF. Fifteen SSNHL patients with FEF and 20 healthy controls (HCs) were recruited and underwent 18F-SynVesT-1 static PET. Standardized uptake values ratios (SUVr) of 18F-SynVesT-1 were computed between regions of interest.ResultsThe occurrence of FEF was not related to the audiogram type or severity of hearing loss. There was a positive correlation between the degree of FEF and the degree of hearing loss. Recovery from FEF was not related to the audiogram shape, the degree of hearing loss or recovery. Fifteen SSNHL patients with FEF had relatively low 18F-SynVesT-1 uptake in the right middle frontal gyrus, right inferior frontal gyrus, right middle temporal gyrus, bilateral parietal lobe sub-gyral and left medial frontal gyrus, as compared with HCs. There was no relatively high 18F-SynVesT-1 uptake in the cerebral cortex.ConclusionThe occurrence and recovery of FEF in SSNHL patients are not related to the classification, degree and recovery of hearing loss. The 18F-SynVesT-1 uptake in the cerebral cortex of patients experiencing SSNHL and FEF has shown alterations. This indicates that FEF may be related to cortical reorganization after the sudden impairment of unilateral auditory input.
{"title":"Characteristics of ear fullness and synaptic loss in ear fullness revealed by SV2A positron emission tomographycortical","authors":"En Zhou, Xuping Xiao, Bin Liu, Zhiqiang Tan, JiaYu Zhong","doi":"10.3389/fnmol.2024.1451226","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1451226","url":null,"abstract":"ObjectiveStudies on feeling of ear fullness (FEF) related to sudden sensorineural hearing loss(SSNHL) are limited. The mechanisms of FEF are unclear. This study aimed to explore the characteristics and related brain activation of SSNHL with FEF.MethodsA total of 269 SSNHL patients were prospectively observed and divided into two groups, with FEF and without FEF. Fifteen SSNHL patients with FEF and 20 healthy controls (HCs) were recruited and underwent 18F-SynVesT-1 static PET. Standardized uptake values ratios (SUVr) of 18F-SynVesT-1 were computed between regions of interest.ResultsThe occurrence of FEF was not related to the audiogram type or severity of hearing loss. There was a positive correlation between the degree of FEF and the degree of hearing loss. Recovery from FEF was not related to the audiogram shape, the degree of hearing loss or recovery. Fifteen SSNHL patients with FEF had relatively low 18F-SynVesT-1 uptake in the right middle frontal gyrus, right inferior frontal gyrus, right middle temporal gyrus, bilateral parietal lobe sub-gyral and left medial frontal gyrus, as compared with HCs. There was no relatively high 18F-SynVesT-1 uptake in the cerebral cortex.ConclusionThe occurrence and recovery of FEF in SSNHL patients are not related to the classification, degree and recovery of hearing loss. The 18F-SynVesT-1 uptake in the cerebral cortex of patients experiencing SSNHL and FEF has shown alterations. This indicates that FEF may be related to cortical reorganization after the sudden impairment of unilateral auditory input.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"128 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.3389/fnmol.2024.1459098
Kevin M. Braunscheidel, George Voren, Christie D. Fowler, Qun Lu, Alexander Kuryatov, Michael D. Cameron, Ines Ibañez-Tallon, Jon M. Lindstrom, Theodore M. Kamenecka, Paul J. Kenny
Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents. 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) enhances the activity of α4β2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of α4/α4 and α4/α5 subunits. The NS9283 derivative 3-(5-(pyridin-3-yl)-2H-tetrazol-2-yl)benzonitrile (SR9883) similarly enhanced the effect of nicotine on α4β2* nAChR stoichiometries that contain low-affinity agonist binding sites, with EC50 values ranging from 0.2–0.4 μM. SR9883 had no effect on any stoichiometry of α3β2* and α3β4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg−1) and oral (10–20 mg kg−1) administration and penetrated into the brain. When administered alone, SR9883 (5–10 mg kg−1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg−1) decreased responding for intravenous nicotine infusions (0.03 mg kg−1 per infusion) but had no effect on responding for food rewards in rats. Together, these data suggest that SR9883 is useful for investigating physiological and behavioral processes regulated by certain stoichiometries α4β2* nAChRs, including the motivational properties of nicotine. SR9883 or related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.
{"title":"SR9883 is a novel small-molecule enhancer of α4β2* nicotinic acetylcholine receptor signaling that decreases intravenous nicotine self-administration in rats","authors":"Kevin M. Braunscheidel, George Voren, Christie D. Fowler, Qun Lu, Alexander Kuryatov, Michael D. Cameron, Ines Ibañez-Tallon, Jon M. Lindstrom, Theodore M. Kamenecka, Paul J. Kenny","doi":"10.3389/fnmol.2024.1459098","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1459098","url":null,"abstract":"Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents. 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) enhances the activity of α4β2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of α4/α4 and α4/α5 subunits. The NS9283 derivative 3-(5-(pyridin-3-yl)-2H-tetrazol-2-yl)benzonitrile (SR9883) similarly enhanced the effect of nicotine on α4β2* nAChR stoichiometries that contain low-affinity agonist binding sites, with EC<jats:sub>50</jats:sub> values ranging from 0.2–0.4 μM. SR9883 had no effect on any stoichiometry of α3β2* and α3β4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg<jats:sup>−1</jats:sup>) and oral (10–20 mg kg<jats:sup>−1</jats:sup>) administration and penetrated into the brain. When administered alone, SR9883 (5–10 mg kg<jats:sup>−1</jats:sup>) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg<jats:sup>−1</jats:sup>) decreased responding for intravenous nicotine infusions (0.03 mg kg<jats:sup>−1</jats:sup> per infusion) but had no effect on responding for food rewards in rats. Together, these data suggest that SR9883 is useful for investigating physiological and behavioral processes regulated by certain stoichiometries α4β2* nAChRs, including the motivational properties of nicotine. SR9883 or related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"281 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.3389/fnmol.2024.1431549
Ofir Sade, Daphna Fischel, Noa Barak-Broner, Shir Halevi, Irit Gottfried, Dana Bar-On, Stefan Sachs, Anat Mirelman, Avner Thaler, Aviv Gour, Meir Kestenbaum, Mali Gana Weisz, Saar Anis, Claudio Soto, Melanie Shanie Roitman, Shimon Shahar, Kathrin Doppler, Markus Sauer, Nir Giladi, Nirit Lev, Roy N. Alcalay, Sharon Hassin-Baer, Uri Ashery
Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (dSTORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto dSTORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001–0.1 molecules/nm2. Our dSTORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status.
{"title":"A novel super-resolution microscopy platform for cutaneous alpha-synuclein detection in Parkinson’s disease","authors":"Ofir Sade, Daphna Fischel, Noa Barak-Broner, Shir Halevi, Irit Gottfried, Dana Bar-On, Stefan Sachs, Anat Mirelman, Avner Thaler, Aviv Gour, Meir Kestenbaum, Mali Gana Weisz, Saar Anis, Claudio Soto, Melanie Shanie Roitman, Shimon Shahar, Kathrin Doppler, Markus Sauer, Nir Giladi, Nirit Lev, Roy N. Alcalay, Sharon Hassin-Baer, Uri Ashery","doi":"10.3389/fnmol.2024.1431549","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1431549","url":null,"abstract":"Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (<jats:italic>d</jats:italic>STORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto <jats:italic>d</jats:italic>STORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001–0.1 molecules/nm<jats:sup>2</jats:sup>. Our <jats:italic>d</jats:italic>STORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"7 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IntroductionPrimary dysmenorrhea (PDM), characterized by cyclic pain, may involve pain modulation within the reward system (RS). The Catechol-O-methyltransferase (COMT) Val158Met polymorphism, which significantly influences dopamine activity, is linked to the regulation of both acute and chronic pain. This study examines the differential neurodynamic modulation in the RS associated with COMT Val158Met polymorphisms during menstrual pain among PDM subjects.MethodNinety-one PDM subjects underwent resting-state fMRI during menstruation and were genotyped for COMT Val158Met polymorphisms. The amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses were used to assess the RS response. Psychological evaluations included the McGill Pain Questionnaire, Pain Catastrophizing Scale, Beck Anxiety Inventory, and Beck Depression Inventory.ResultVal/Val homozygotes (n = 50) and Met carriers (n = 41) showed no significant differences in McGill Pain Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory. However, Met carriers exhibited lower scores on the Pain Catastrophizing Scale. Distinct FC patterns was observed between Val/Val homozygotes and Met carriers, specifically between the nucleus accumbens (NAc) and prefrontal cortex, NAc and inferior parietal lobe, ventral tegmental area (VTA) and prefrontal cortex, VTA and precentral gyrus, and VTA and superior parietal lobe. Only Met carriers showed significant correlations between ALFF and FC values of the NAc and VTA with pain-related metrics (McGill Pain Questionnaire and Pain Catastrophizing Scale scores). NAc ALFF and NAc-prefrontal cortex FC values positively correlated with pain-related metrics, while VTA ALFF and VTA-prefrontal cortex and VTA-superior parietal lobe FC values negatively correlated with pain-related metrics.DiscussionThis study reveals that the COMT Val158Met polymorphism results in genotype-specific functional changes in the brain’s RS during menstrual pain. In Met carriers, engagement of these regions is potentially linked to motivational reward-seeking and top-down modulation. This polymorphism likely influences the RS’s responses, significantly contributing to individual differences in pain regulation.
{"title":"Reward system neurodynamics during menstrual pain modulated by COMT Val158Met polymorphisms","authors":"Pei-Shan Hsu, Ching-Hsiung Liu, Ching-Ju Yang, Lin-Chien Lee, Wei-Chi Li, Hsiang-Tai Chao, Ming-Wei Lin, Li-Fen Chen, Jen-Chuen Hsieh","doi":"10.3389/fnmol.2024.1457602","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1457602","url":null,"abstract":"IntroductionPrimary dysmenorrhea (PDM), characterized by cyclic pain, may involve pain modulation within the reward system (RS). The Catechol-O-methyltransferase (<jats:italic>COMT</jats:italic>) Val158Met polymorphism, which significantly influences dopamine activity, is linked to the regulation of both acute and chronic pain. This study examines the differential neurodynamic modulation in the RS associated with <jats:italic>COMT</jats:italic> Val158Met polymorphisms during menstrual pain among PDM subjects.MethodNinety-one PDM subjects underwent resting-state fMRI during menstruation and were genotyped for <jats:italic>COMT</jats:italic> Val158Met polymorphisms. The amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses were used to assess the RS response. Psychological evaluations included the McGill Pain Questionnaire, Pain Catastrophizing Scale, Beck Anxiety Inventory, and Beck Depression Inventory.ResultVal/Val homozygotes (<jats:italic>n</jats:italic> = 50) and Met carriers (<jats:italic>n</jats:italic> = 41) showed no significant differences in McGill Pain Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory. However, Met carriers exhibited lower scores on the Pain Catastrophizing Scale. Distinct FC patterns was observed between Val/Val homozygotes and Met carriers, specifically between the nucleus accumbens (NAc) and prefrontal cortex, NAc and inferior parietal lobe, ventral tegmental area (VTA) and prefrontal cortex, VTA and precentral gyrus, and VTA and superior parietal lobe. Only Met carriers showed significant correlations between ALFF and FC values of the NAc and VTA with pain-related metrics (McGill Pain Questionnaire and Pain Catastrophizing Scale scores). NAc ALFF and NAc-prefrontal cortex FC values positively correlated with pain-related metrics, while VTA ALFF and VTA-prefrontal cortex and VTA-superior parietal lobe FC values negatively correlated with pain-related metrics.DiscussionThis study reveals that the <jats:italic>COMT</jats:italic> Val158Met polymorphism results in genotype-specific functional changes in the brain’s RS during menstrual pain. In Met carriers, engagement of these regions is potentially linked to motivational reward-seeking and top-down modulation. This polymorphism likely influences the RS’s responses, significantly contributing to individual differences in pain regulation.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"9 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.3389/fnmol.2024.1417961
Veronica Noches, Danae Campos-Melo, Cristian A. Droppelmann, Michael J. Strong
The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.
肌萎缩性脊髓侧索硬化症（ALS）的运动神经元会逐渐退化，同时会形成多种细胞质和细胞核神经元内含物（蛋白质聚集体），这些内含物大多含有 RNA 结合蛋白，如 TAR DNA 结合蛋白 43（TDP-43）或肉瘤中的融合蛋白/脂肪肉瘤中的转移蛋白（FUS/TLS）。这一过程通常是由无膜细胞器中蛋白质的液固相分离驱动的，从而产生病理生物分子凝聚物。这些蛋白质聚集体的形成表明，mRNA 的表达或相关蛋白质的水平发生了根本性的改变。考虑到表观基因组在基因表达中的作用，DNA甲基化、组蛋白修饰、染色质重塑、非编码RNA和RNA修饰的改变与理解这一病理过程如何发生作用高度相关。在这篇综述中，我们探讨了将表观遗传机制与 ALS 蛋白质聚集体的形成联系起来的证据。我们认为，进一步了解表观基因组的作用以及表观基因组如何与 ALS 病理 LLPS 的形成相互关联，将为我们提供一个极具吸引力的治疗目标。
{"title":"Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis","authors":"Veronica Noches, Danae Campos-Melo, Cristian A. Droppelmann, Michael J. Strong","doi":"10.3389/fnmol.2024.1417961","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1417961","url":null,"abstract":"The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"2 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：