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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}
Pub Date : 2024-09-03DOI: 10.3389/fnmol.2024.1461272
Wei Wan, Nan Wang
IntroductionThe neuronal nitric oxide synthase (nNOS) subtype of nitric oxide synthase (NOS) is an enzyme required for learning and memory. Overactivation of nNOS can lead to oxidative/nitrite stress, which is complicit in the pathophysiology of various neurological and psychiatric disorders. Previous studies have shown that calmodulin (CaM) forms complexes with Ca2+ and binds to the calmodulin-binding domain (CaMBD) of nNOS, thereby upregulating its catalytic activity in hippocampal neurons. To date, there has been no explanation for the non-covalent interactions in the CaMBD-CaM binding structure model of nNOS.MethodsIn this study, we aimed to investigate the intrinsic factors involved in the binding of CaM to NOS-CaMBD and designed interfering peptides based on the N0 peptide structure of the original nNOS-CaMBD sequence: N1 (obtained from the L734F mutation), N2 (obtained from the F731Y and F740Y mutations), and N3 (obtained from the F731L, V738L, and F740L mutations). We employed homology modeling to construct six CaM-peptide complex models, aiming to elucidate the roles of key amino acid residues within the N0 peptide in its interaction with CaM by means of molecular dynamics simulations. The effect of the peptides on the activation and release of NO by nNOS in neurons was assessed using murine primary neuronal cells.ResultsWhen measuring neuronal NO content, it was found that adding N2 and N3 to cultivated neurons significantly increased nNOS activity, leading to the increased NO production. We found that interfering peptides could stably bind to CaM. Among them, N2 and CaM exhibited the strongest binding ability, indicating that the polarized benzene ring significantly enhanced the binding between nNOS-CaMBD and CaM. Conversely, the binding ability between N0 and CaM was the weakest, as they exhibited the worst polar contact, weakest hydrogen bonding, and the lowest binding free energy. The simulation results also highlighted several important amino acid residues: The K76 of CaM plays an important role in polar contact and hydrogen bonding formation, the L734 residue suppressed model flexibility to a certain extent and had an adverse effect on the overall binding free energy of the model. These results, compared with the results of cellular NO content, a preliminary verification of the antagonistic competitive mechanism between CaM allosteric activation of nNOS and SUMOylation hyperactivation was performed.DiscussionIn summary, this study explored the ability and mode of action of key residues in nNOS-CaMBD on the binding of interfering peptides to CaM, thereby providing new structural perspectives for the activation of nNOS by CaM and recommendations for drug design targeting the specific inhibition of nNOS.
{"title":"Polarized benzene rings can promote the interaction between CaM and the CaMBD region of nNOS","authors":"Wei Wan, Nan Wang","doi":"10.3389/fnmol.2024.1461272","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1461272","url":null,"abstract":"IntroductionThe neuronal nitric oxide synthase (nNOS) subtype of nitric oxide synthase (NOS) is an enzyme required for learning and memory. Overactivation of nNOS can lead to oxidative/nitrite stress, which is complicit in the pathophysiology of various neurological and psychiatric disorders. Previous studies have shown that calmodulin (CaM) forms complexes with Ca<jats:sup>2+</jats:sup> and binds to the calmodulin-binding domain (CaMBD) of nNOS, thereby upregulating its catalytic activity in hippocampal neurons. To date, there has been no explanation for the non-covalent interactions in the CaMBD-CaM binding structure model of nNOS.MethodsIn this study, we aimed to investigate the intrinsic factors involved in the binding of CaM to NOS-CaMBD and designed interfering peptides based on the N0 peptide structure of the original nNOS-CaMBD sequence: N1 (obtained from the L734F mutation), N2 (obtained from the F731Y and F740Y mutations), and N3 (obtained from the F731L, V738L, and F740L mutations). We employed homology modeling to construct six CaM-peptide complex models, aiming to elucidate the roles of key amino acid residues within the N0 peptide in its interaction with CaM by means of molecular dynamics simulations. The effect of the peptides on the activation and release of NO by nNOS in neurons was assessed using murine primary neuronal cells.ResultsWhen measuring neuronal NO content, it was found that adding N2 and N3 to cultivated neurons significantly increased nNOS activity, leading to the increased NO production. We found that interfering peptides could stably bind to CaM. Among them, N2 and CaM exhibited the strongest binding ability, indicating that the polarized benzene ring significantly enhanced the binding between nNOS-CaMBD and CaM. Conversely, the binding ability between N0 and CaM was the weakest, as they exhibited the worst polar contact, weakest hydrogen bonding, and the lowest binding free energy. The simulation results also highlighted several important amino acid residues: The K76 of CaM plays an important role in polar contact and hydrogen bonding formation, the L734 residue suppressed model flexibility to a certain extent and had an adverse effect on the overall binding free energy of the model. These results, compared with the results of cellular NO content, a preliminary verification of the antagonistic competitive mechanism between CaM allosteric activation of nNOS and SUMOylation hyperactivation was performed.DiscussionIn summary, this study explored the ability and mode of action of key residues in nNOS-CaMBD on the binding of interfering peptides to CaM, thereby providing new structural perspectives for the activation of nNOS by CaM and recommendations for drug design targeting the specific inhibition of nNOS.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215284","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 : 2024-09-02DOI: 10.3389/fnmol.2024.1398048
Nagore Elu, Srividya Subash, Susana R. Louros
Ubiquitination is one of the most conserved post-translational modifications and together with mRNA translation contributes to cellular protein homeostasis (proteostasis). Temporal and spatial regulation of proteostasis is particularly important during synaptic plasticity, when translation of specific mRNAs requires tight regulation. Mutations in genes encoding regulators of mRNA translation and in ubiquitin ligases have been associated with several neurodevelopmental disorders. RNA metabolism and translation are regulated by RNA-binding proteins, critical for the spatial and temporal control of translation in neurons. Several ubiquitin ligases also regulate RNA-dependent mechanisms in neurons, with numerous ubiquitination events described in splicing factors and ribosomal proteins. Here we will explore how ubiquitination regulates translation in neurons, from RNA biogenesis to alternative splicing and how dysregulation of ubiquitin signaling can be the underlying cause of pathology in neurodevelopmental disorders, such as Fragile X syndrome. Finally we propose that targeting ubiquitin signaling is an attractive novel therapeutic strategy for neurodevelopmental disorders where mRNA translation and ubiquitin signaling are disrupted.
{"title":"Crosstalk between ubiquitination and translation in neurodevelopmental disorders","authors":"Nagore Elu, Srividya Subash, Susana R. Louros","doi":"10.3389/fnmol.2024.1398048","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1398048","url":null,"abstract":"Ubiquitination is one of the most conserved post-translational modifications and together with mRNA translation contributes to cellular protein homeostasis (proteostasis). Temporal and spatial regulation of proteostasis is particularly important during synaptic plasticity, when translation of specific mRNAs requires tight regulation. Mutations in genes encoding regulators of mRNA translation and in ubiquitin ligases have been associated with several neurodevelopmental disorders. RNA metabolism and translation are regulated by RNA-binding proteins, critical for the spatial and temporal control of translation in neurons. Several ubiquitin ligases also regulate RNA-dependent mechanisms in neurons, with numerous ubiquitination events described in splicing factors and ribosomal proteins. Here we will explore how ubiquitination regulates translation in neurons, from RNA biogenesis to alternative splicing and how dysregulation of ubiquitin signaling can be the underlying cause of pathology in neurodevelopmental disorders, such as Fragile X syndrome. Finally we propose that targeting ubiquitin signaling is an attractive novel therapeutic strategy for neurodevelopmental disorders where mRNA translation and ubiquitin signaling are disrupted.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215282","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}
IntroductionNeuropathic pain (NP) conditions arising from injuries to the nervous system due to trauma, disease, or neurotoxins are chronic, severe, debilitating, and exceedingly difficult to treat. However, the mechanisms of NP are not yet clear. Here we explored the role of Dock4, an atypical Rac1 GEF, in the development of NP.MethodsMechanical allodynia was assessed as paw withdrawal threshold by a dynamic plantar aesthesiometer. Immunofluorescence staining was conducted to investigate the expression and localization of Dock4, Rac1 and GluN2B. Quantitative analysis of Dock4, Rac1 and GluN2B were determined by qRT-PCR and Western blot assay. Spontaneous excitatory and inhibitory postsynaptic currents in spinal cord slices were examined using whole cell patch clam. Dendritic spine remodeling and synaptogenesis were detected in cultured dorsal spinal neurons.Results and discussionWe found that SNL caused markedly mechanical allodynia accompanied by increase of Dock4, GTP-Rac1and GluN2B, which was prevented by knockdown of Dock4. Electrophysiological tests showed that SNL facilitated excitatory synaptic transmission, however, this was also inhibited by Dock RNAi-LV. Moreover, knockdown of Dock4 prevented dendritic growth and synaptogenesis.ConclusionIn summary, our data indicated that Dock4 facilitated excitatory synaptic transmission by promoting the expression of GluN2B at the synaptic site and synaptogenesis, leading to the occurrence of NP.
{"title":"Dock4 contributes to neuropathic pain by regulating spinal synaptic plasticity in mice","authors":"Qiaochu Fu, Hongyi Li, Zhuanxu Zhu, Wencui Li, Zhihua Ruan, Ruijie Chang, Huixia Wei, Xueqin Xu, Xunliang Xu, Yanqiong Wu","doi":"10.3389/fnmol.2024.1417567","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1417567","url":null,"abstract":"IntroductionNeuropathic pain (NP) conditions arising from injuries to the nervous system due to trauma, disease, or neurotoxins are chronic, severe, debilitating, and exceedingly difficult to treat. However, the mechanisms of NP are not yet clear. Here we explored the role of Dock4, an atypical Rac1 GEF, in the development of NP.MethodsMechanical allodynia was assessed as paw withdrawal threshold by a dynamic plantar aesthesiometer. Immunofluorescence staining was conducted to investigate the expression and localization of Dock4, Rac1 and GluN2B. Quantitative analysis of Dock4, Rac1 and GluN2B were determined by qRT-PCR and Western blot assay. Spontaneous excitatory and inhibitory postsynaptic currents in spinal cord slices were examined using whole cell patch clam. Dendritic spine remodeling and synaptogenesis were detected in cultured dorsal spinal neurons.Results and discussionWe found that SNL caused markedly mechanical allodynia accompanied by increase of Dock4, GTP-Rac1and GluN2B, which was prevented by knockdown of Dock4. Electrophysiological tests showed that SNL facilitated excitatory synaptic transmission, however, this was also inhibited by Dock RNAi-LV. Moreover, knockdown of Dock4 prevented dendritic growth and synaptogenesis.ConclusionIn summary, our data indicated that Dock4 facilitated excitatory synaptic transmission by promoting the expression of GluN2B at the synaptic site and synaptogenesis, leading to the occurrence of NP.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215286","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 : 2024-08-29DOI: 10.3389/fnmol.2024.1463437
Xiaoran Wei, Jack L. Browning, Michelle L. Olsen
Brain derived neurotrophic factor (BDNF) is the most studied trophic factor in the central nervous system (CNS), and its role in the maturation of neurons, including synapse development and maintenance has been investigated intensely for over three decades. The primary receptor for BDNF is the tropomyosin receptor kinase B (TrkB), which is broadly expressed as two primary isoforms in the brain; the full length TrkB (TrkB.FL) receptor, expressed mainly in neurons and the truncated TrkB (TrkB.T1) receptor. We recently demonstrated that TrkB.T1 is predominately expressed in astrocytes, and appears critical for astrocyte morphological maturation. Given the critical role of BDNF/TrkB pathway in healthy brain development and mature CNS function, we aimed to identify molecular underpinnings of cell-type specific expression of each TrkB isoform. Using Nanopore sequencing which enables direct, long read sequencing of native DNA, we profiled DNA methylation patterns of the entire TrkB gene, Ntrk2, in both neurons and astrocytes. Here, we identified robust differences in cell-type specific isoform expression associated with significantly different methylation patterns of the Ntrk2 gene in each cell type. Notably, astrocytes demonstrated lower 5mC methylation, and higher 5hmC across the entire gene when compared to neurons, including differentially methylated sites (DMSs) found in regions flanking the unique TrkB.T1 protein coding sequence (CDS). These data suggest DNA methylation patterns may provide instruction for isoform specific TrkB expression across unique CNS cell types.
{"title":"Neuron and astrocyte specific 5mC and 5hmC signatures of BDNF’s receptor, TrkB","authors":"Xiaoran Wei, Jack L. Browning, Michelle L. Olsen","doi":"10.3389/fnmol.2024.1463437","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1463437","url":null,"abstract":"Brain derived neurotrophic factor (BDNF) is the most studied trophic factor in the central nervous system (CNS), and its role in the maturation of neurons, including synapse development and maintenance has been investigated intensely for over three decades. The primary receptor for BDNF is the tropomyosin receptor kinase B (TrkB), which is broadly expressed as two primary isoforms in the brain; the full length TrkB (TrkB.FL) receptor, expressed mainly in neurons and the truncated TrkB (TrkB.T1) receptor. We recently demonstrated that TrkB.T1 is predominately expressed in astrocytes, and appears critical for astrocyte morphological maturation. Given the critical role of BDNF/TrkB pathway in healthy brain development and mature CNS function, we aimed to identify molecular underpinnings of cell-type specific expression of each TrkB isoform. Using Nanopore sequencing which enables direct, long read sequencing of native DNA, we profiled DNA methylation patterns of the entire TrkB gene, <jats:italic>Ntrk2</jats:italic>, in both neurons and astrocytes. Here, we identified robust differences in cell-type specific isoform expression associated with significantly different methylation patterns of the <jats:italic>Ntrk2</jats:italic> gene in each cell type. Notably, astrocytes demonstrated lower 5mC methylation, and higher 5hmC across the entire gene when compared to neurons, including differentially methylated sites (DMSs) found in regions flanking the unique TrkB.T1 protein coding sequence (CDS). These data suggest DNA methylation patterns may provide instruction for isoform specific TrkB expression across unique CNS cell types.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215289","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：